Therapeutic compounds, compositions and methods of use thereof

ABSTRACT

Compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     and salts thereof, and methods of use as Janus kinase inhibitors are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/EP2017/060349, filed May 2, 2017, which claims priority toInternational Application No. PCT/CN2016/081093, filed May 5, 2016,International Application No. PCT/CN2016/081566, filed May 10, 2016, andU.S. provisional application Ser. No. 62/418,500, filed Nov. 7, 2016,each of which is incorporated by reference in its entirety.

FIELD OF THE INVENTION

The field of the invention pertains to compounds that are inhibitors ofa Janus kinase, such as JAK1, as well as compositions containing thesecompounds, and methods of use including, but not limited to, diagnosisor treatment of patients suffering from a condition responsive to theinhibition of a JAK kinase.

BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions,including many aspects of inflammation and immunity. Janus kinases(JAK), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic proteinkinases that associate with type I and type II cytokine receptors andregulate cytokine signal transduction. Cytokine engagement with cognatereceptors triggers activation of receptor associated JAKs and this leadsto JAK-mediated tyrosine phosphorylation of signal transducer andactivator of transcription (STAT) proteins and ultimatelytranscriptional activation of specific gene sets (Schindler et al.,2007, J. Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broadpatterns of gene expression, while JAK3 expression is limited toleukocytes. Cytokine receptors are typically functional as heterodimers,and as a result, more than one type of JAK kinase is usually associatedwith cytokine receptor complexes. The specific JAKs associated withdifferent cytokine receptor complexes have been determined in many casesthrough genetic studies and corroborated by other experimental evidence.Exemplary therapeutic benefits of the inhibition of JAK enzymes arediscussed, for example, in International Application No. WO 2013/014567.

JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:1603-1607). Genetic andbiochemical studies have shown that JAK1 is functionally and physicallyassociated with the type I interferon (e.g., IFNalpha), type IIinterferon (e.g., IFNgamma), and IL-2 and IL-6 cytokine receptorcomplexes (Kisseleva et al., 2002, Gene 285:1-24; Levy et al., 2005,Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). JAK1 knockout mice die perinatally due to defectsin LIF receptor signalling (Kisseleva et al., 2002, Gene 285:1-24;O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Characterization oftissues derived from JAK1 knockout mice demonstrated critical roles forthis kinase in the IFN, IL-10, IL-2/IL-4 and IL-6 pathways. A humanizedmonoclonal antibody targeting the IL-6 pathway (Tocilizumab) is approvedin many countries for the treatment of moderate-to-severe rheumatoidarthritis (Scheinecker et al., 2009, Nat. Rev. Drug Discov. 8:273-274).

CD4 T cells play an important role in asthma pathogenesis through theproduction of TH2 cytokines within the lung, including IL-4, IL-9 andIL-13 (Cohn et al., 2004, Annu. Rev. Immunol. 22:789-815). IL-4 andIL-13 induce increased mucus production, recruitment of eosinophils tothe lung, and increased production of IgE (Kasaian et al., 2008,Biochem. Pharmacol. 76(2): 147-155). IL-9 leads to mast cell activation,which exacerbates the asthma symptoms (Kearley et al., 2011, Am. J.Resp. Crit. Care Med., 183(7): 865-875). The IL-4Rα chain activates JAK1and binds to either IL-4 or IL-13 when combined with the common gammachain or the IL-13Rα1 chain, respectively (Pernis et al., 2002, J. Clin.Invest. 109(10):1279-1283). The common gamma chain can also combine withIL-9Rα to bind to IL-9, and IL-9Rα activates JAK1 as well (Demoulin etal., 1996, Mol. Cell Biol. 16(9):4710-4716). While the common gammachain activates JAK3, it has been shown that JAK1 is dominant over JAK3,and inhibition of JAK1 is sufficient to inactivate signaling through thecommon gamma chain despite JAK3 activity (Haan et al., 2011, Chem. Biol.18(3):314-323). Inhibition of IL-4, IL-13 and IL-9 signaling by blockingthe JAK/STAT signaling pathway can alleviate asthmatic symptoms inpre-clinical lung inflammation models (Mathew et al., 2001, J. Exp. Med.193(9): 1087-1096; Kudlacz et. al., 2008, Eur. J. Pharmacol. 582(1-3):154-161).

Biochemical and genetic studies have shown an association between JAK2and single-chain (e.g., EPO), IL-3 and interferon gamma cytokinereceptor families (Kisseleva et al., 2002, Gene 285:1-24; Levy et al.,2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al., 2002, Cell,109 (suppl.): S121-S131). Consistent with this, JAK2 knockout mice dieof anemia (O'Shea et al., 2002, Cell, 109 (suppl.): S121-S131). Kinaseactivating mutations in JAK2 (e.g., JAK2 V617F) are associated withmyeloproliferative disorders in humans.

JAK3 associates exclusively with the gamma common cytokine receptorchain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21cytokine receptor complexes. JAK3 is critical for lymphoid celldevelopment and proliferation and mutations in JAK3 result in severecombined immunodeficiency (SCID) (O'Shea et al., 2002, Cell, 109(suppl.): S121-S131). Based on its role in regulating lymphocytes, JAK3and JAK3-mediated pathways have been targeted for immunosuppressiveindications (e.g., transplantation rejection and rheumatoid arthritis)(Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelianet al., 2003, Science 302: 875-878).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6,IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al.,2002, Gene 285:1-24; Watford, W. T. & O'Shea, J. J., 2006, Immunity25:695-697). Consistent with this, primary cells derived from a TYK2deficient human are defective in type I interferon, IL-6, IL-10, IL-12and IL-23 signalling. A fully human monoclonal antibody targeting theshared p40 subunit of the IL-12 and IL-23 cytokines (Ustekinumab) isapproved in several countries for the treatment of moderate-to-severeplaque psoriasis (Krueger et al., 2007, N. Engl. J. Med. 356:580-92;Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356). In addition, anantibody targeting the IL-12 and IL-23 pathways underwent clinicaltrials for treating Crohn's Disease (Mannon et al., 2004, N. Engl. J.Med. 351:2069-79).

Currently there remains a need for additional compounds that areinhibitors of Janus kinases. For example, there is a need for compoundsthat possess useful potency as inhibitors of one or more Janus kinase(e.g., JAK1) in combination with other pharmacological properties thatare necessary to achieve a useful therapeutic benefit. For example,there is a need for potent compounds that demonstrate selectivity forone Janus kinase over other kinases in general (e.g., selectivity forJAK1 over other kinases such as leucine-rich repeat kinase 2 LRRK2).There is also a need for potent compounds that demonstrate selectivityfor one Janus kinase over other Janus kinases (e.g., selectivity forJAK1 over other Janus kinases). Kinases demonstrating selectivity forJAK1 could provide a therapeutic benefit, with fewer side effects, inconditions responsive to the inhibition of JAK1. Additionally there iscurrently a need for potent JAK1 inhibitors that possess otherproperties (e.g., melting point, pK, solubility, etc.) necessary forformulation and administration by inhalation. Such compounds would beparticularly useful for treating conditions such as, for example,asthma.

SUMMARY OF INVENTION

One aspect of the invention includes a compound of the invention, whichis a compound of Formula (I):

or a salt thereof, wherein:

R¹ and R^(1a) taken together with the atom to which they are attachedform a 3-10 membered carbocycle optionally substituted with R^(a) andoptionally substituted with R^(b); or R¹ and R^(1a) taken together withthe atom to which they are attached form a 3-15 membered heterocycleoptionally substituted with R^(c) and optionally substituted with R^(d);

R² is —NR^(e)R^(f);

R³ is —CH₃ or —CN;

R^(a) is —NR^(r)R^(s) or —OR^(r);

each R^(b) is independently selected from the group consisting of halo,cyano, hydroxy, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, —NH₂, —NHCH₃, —N(CH₃)₂,—SH, and —SCH₃, wherein any C₁-C₆alkyl, and C₁-C₆alkoxy is optionallysubstituted with halo, cyano, hydroxy, oxo, C₁₋₃alkyl, C₁₋₃alkoxy, —NH₂,—NHCH₃, —N(CH₃)₂, —SH, or —SCH₃, wherein any C₁₋₃alkyl and C₁₋₃alkoxy isoptionally substituted with halo, hydroxy, cyano or oxo;

R^(c) is —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 3-10membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or5-10 membered heteroaryl, wherein any C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl of R^(c) is optionally substituted with R^(x);

each R^(d) is independently selected from the group consisting of halo,cyano, C₁-C₆alkyl, and C₁-C₆alkoxy, wherein any C₁-C₆alkyl, andC₁-C₆alkoxy is optionally substituted with halo, hydroxy, cyano or oxo;

R^(e) is H or C₁-C₄alkyl;

R^(f) is —C(═O)—R^(g), or aryl that is optionally substituted with oneor more groups selected from the group consisting of halo, cyano, nitro,trifluoromethyl, trifluoromethoxy, —S(O)₂R^(h), and —P(═O)(OR^(k))₂;

R^(g) is H, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy, —NR^(t)R^(u), or a 3-10membered carbocyclyl that is optionally substituted with halo, hydroxy,cyano, oxo, C₁-C₃alkyl, C₂-C₃alkynyl, 6-10 membered aryl, 5-6 memberedheteroaryl, or 3-5 membered carbocyclyl, wherein any C₁-C₃alkyl, 6-10membered aryl, 5-6 membered heteroaryl, or 3-5 membered carbocyclyl isoptionally substituted with halo, hydroxy, cyano, or C₁-C₃alkyl;

each R^(h) is independently selected from the group consisting ofC₁-C₆alkyl that is optionally substituted with halo;

each R^(k) is independently selected from the group consisting of H andC₁-C₆alkyl that is optionally substituted with halo;

R^(m) and R^(n) are independently selected from the group consisting ofhydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl, and C₁-C₆alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl, and C₁-C₆alkyl of R^(m) and R^(n) isoptionally substituted with R^(w); or R^(m) and R^(n) are taken togetherwith the atom to which they are attached to form a 3-8 memberedheterocyclyl that is optionally substituted with R^(w);

each R^(r) and R^(s) is independently selected from the group consistingof hydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl and C₁-C₃alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl and C₁-C₃alkyl of R^(r) and R^(s) is optionallysubstituted with R^(v); or R^(r) and R^(s) are taken together with theatom to which they are attached to form a 3-8 membered heterocyclyl or5-10 membered heteroaryl, which 3-8 membered heterocyclyl and 5-10membered heteroaryl is to optionally substituted with R^(v);

R^(t) and R^(u) are independently selected from the group consisting ofhydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl and C₁-C₃alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl and C₁-C₃alkyl of R^(t) and R^(u) is optionallysubstituted with halo, hydroxy, cyano or oxo; or R^(t) and R^(u) aretaken together with the atom to which they are attached to form a 3-6membered heterocyclyl, optionally substituted with halo, hydroxy, cyanoor oxo, or C₁-C₆alkyl that is optionally substituted with halo, hydroxy,cyano or oxo;

each R^(v) is independently selected from the group consisting of halo,hydroxy, cyano, oxo, 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, 3-6 membered carbocyclyl, 3-6membered heterocyclyl, (6-10 membered aryl)-O—, (5-10 memberedheteroaryl)-O—, (3-6 membered carbocyclyl)-O—, (3-6 memberedheterocyclyl)-O—, and C₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10membered heteroaryl, C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl, (6-10 membered aryl)-O—, (5-10 membered heteroaryl)-O—,(3-6 membered carbocyclyl)-O—, (3-6 membered heterocyclyl)-O—, andC₁-C₆alkoxy of R^(v) is optionally substituted with halo, hydroxy,cyano, C₁-C₆alkyl, C₂-C₃alkynyl, oxo, 3-6 membered carbocycle, 3-6membered heterocyclyl, C₁-C₆alkoxy, 5-10 membered heteroaryl or 6-10membered aryl, each of which is optionally substituted with halo,hydroxy, cyano, oxo C₁-C₃alkyl or C₁-C₃alkoxy;

each R^(w) is independently selected from the group consisting of halo,hydroxy, cyano, oxo, 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy of R^(w) is optionally substituted with halo, hydroxy,cyano, C₁-C₆alkyl, oxo, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl C₁-C₆alkoxy, 5-10 membered heteroaryl, or 6-10 memberedaryl, each optionally substituted with halo, hydroxy, cyano, oxo,C₁-C₃alkyl or C₁-C₃alkoxy; and

each R^(x) is independently selected from the group consisting of halo,hydroxy, cyano, nitro, oxo, —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m),—C(O)OR^(m), —C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m),—NR^(m)S(O)₁₋₂R^(n), —S(O)₁₋₂NR^(m)R^(n), 3-10 membered carbocyclyl,3-15 membered heterocyclyl, 6-10 membered aryl, and 5-15 memberedheteroaryl, wherein any 3-10 membered carbocyclyl, 3-15 memberedheterocyclyl, 6-10 membered aryl, and 5-15 membered heteroaryl, isoptionally substituted with halo, hydroxy, cyano, nitro, C₂-C₆alkenyl,C₂-C₆alkynyl, —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, oxo, 3-10 membered carbocyclyl, 3-10membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl,wherein any C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 3-10 memberedcarbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10membered heteroaryl is optionally substituted with halo, hydroxy, cyano,oxo, —OR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n),3-6 membered carbocyclyl, 6-10 membered aryl, or C₁-C₆alkyl that isoptionally substituted with halo, hydroxy, cyano, oxo or C₁-C₆alkoxy.

Also provided is a pharmaceutical composition that comprises a compoundof the invention or a salt thereof (e.g., a pharmaceutically acceptablesalt) and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect includes a compound of the invention or a salt thereof(e.g., a pharmaceutically acceptable salt) for use in therapy, such asthe treatment of an inflammatory disease or cancer. The inflammatorydisease may be asthma.

Another aspect includes a method of preventing, treating or lesseningthe severity of a disease or condition responsive to the inhibition of aJanus kinase, such as JAK1 kinase, in a patient. The method can compriseadministering to the patient a therapeutically effective amount of acompound of the invention or a salt thereof (e.g., a pharmaceuticallyacceptable salt).

Another aspect includes the use of a compound of the invention or a saltthereof (e.g., a pharmaceutically acceptable salt) in the manufacture ofa medicament for the treatment of a disease responsive to the inhibitionof a Janus kinase, such as JAK1 kinase.

Another aspect includes a kit for treating a disease or disorderresponsive to the inhibition of a Janus kinase, such as JAK1 kinase. Thekit can comprise a first pharmaceutical composition comprising acompound of the invention or a salt thereof (e.g., a pharmaceuticallyacceptable salt), and instructions for use.

Certain compounds of the invention possess beneficial potency asinhibitors of one or more Janus kinase (e.g., JAK1). Certain compoundsare also, a) selective for one Janus kinase over other kinases, b)selective for JAK1 over other Janus kinases, and/or c) possess otherproperties (e.g., melting point, pK, solubility, etc.) necessary forformulation and administration by inhalation. Certain compounds ofFormula (I) may be particularly useful for treating conditions such asasthma.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Halogen” or “halo” refers to F, C₁, Br or I. Additionally, terms suchas “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.

The term “alkyl” refers to a saturated linear or branched-chainmonovalent hydrocarbon radical, wherein the alkyl radical may beoptionally substituted. In one example, the alkyl radical is one toeighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical isC₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, orC₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups includemethyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl,—CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu,n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl,—CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. In someembodiments, substituents for “optionally substituted alkyls” includeone to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂,NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl,butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo,trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino,SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein thealkyl, phenyl and heterocyclic portions thereof may be optionallysubstituted, such as by one to four instances of substituents selectedfrom this same list.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused toone or more groups, having the number of carbon atoms designated, or ifno number is designated, up to 14 carbon atoms. One example includesaryl groups having 6-14 carbon atoms. Another example includes arylgroups having 6-10 carbon atoms. Examples of aryl groups include phenyl,naphthyl, biphenyl, phenanthrenyl, naphthacenyl,1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, andthe like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.)13^(th) ed. Table 7-2 [1985]). A particular aryl is phenyl. Substitutedphenyl or substituted aryl means a phenyl group or aryl groupsubstituted with one, two, three, four or five substituents, forexample, 1-2, 1-3 or 1-4 substituents, such as chosen from groupsspecified herein (see “optionally substituted” definition), such as F,Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH,CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl,methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl,sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl,piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclicportions thereof may be optionally substituted, such as by one to fourinstances of substituents selected from this same list. Examples of theterm “substituted phenyl” include a mono- or di(halo)phenyl group suchas 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl,2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl,2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- ordi(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl,2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and thelike; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenylgroup, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group suchas 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl,4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; amono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl,3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl,4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protectedcarboxy)phenyl group such 4-carboxyphenyl, a mono- ordi(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; amono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono-or di(N-(methylsulfonylamino))phenyl such as3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl”represents disubstituted phenyl groups where the substituents aredifferent, for example, 3-methyl-4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl,4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl,2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, aswell as trisubstituted phenyl groups where the substituents aredifferent, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino,3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstitutedphenyl groups where the substituents are different such as3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.

The terms “compound(s) of the invention,” and “compound(s) of thepresent invention” and the like, unless otherwise indicated, includecompounds of formulae (I), (Ia), (Ib), (Ic), and (Id), and the compoundsof the Examples herein, including stereoisomers (includingatropisomers), geometric isomers, tautomers, solvates, metabolites,isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugsthereof. In some embodiments, solvates, metabolites, isotopes orprodrugs are excluded, or any combination thereof.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 15 carbon atoms, 6 to 12 or 6 to 10carbon atoms. Aryl includes a phenyl radical. Aryl also includesmultiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4rings) having 9 to 20 carbon atoms in which at least one ring isaromatic and wherein the other rings may be aromatic or not aromatic(i.e., carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and thelike.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e., (C₃-C₇)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic andtetracyclic carbocycles with up to about 20 carbon atoms). The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Forexample, multicyclic carbocyles can be connected to each other via asingle carbon atom to form a spiro connection (e.g., spiropentane,spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fusedconnection (e.g., carbocycles such as decahydronaphthalene, norsabinane,norcarane) or via two non-adjacent carbon atoms to form a bridgedconnection (e.g., norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” can also be optionally substituted withone or more (e.g., 1, 2 or 3) oxo groups. In one embodiment the termcarbocycle includes 3-20 membered carbocycles. In another embodiment theterm carbocycle includes 3-15 membered carbocycles. In anotherembodiment the term carbocycle includes 3-10 membered carbocycles. Inone embodiment the term carbocycle includes a 3-8 membered carbocycle.In one embodiment the term carbocycle includes a 3-6 memberedcarbocycle. In one embodiment the term carbocycle includes a 3-5carbocycle. Non-limiting examples of carbocycles include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl,bicyclo[2.2.1]heptane, pinane, adamantane, norborene, spirocyclic C₅₋₁₂alkane, and 1-cyclohex-3-enyl.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. For example, in certainembodiments, a heteroaryl group has 5 to 20 members, 5 to 15 members, 5to 12 members, or 5 to 10 members. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example a naphthyridinyl such as1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system. It is also to beunderstood that the point of attachment for a heteroaryl or heteroarylmultiple condensed ring system can be at any suitable atom of theheteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroarylsinclude but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl,benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Exemplary heterocycles include but are not limited toazetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. It is also to be understood that the point of attachment ofa multiple condensed ring system (as defined above for a heterocycle)can be at any position of the multiple condensed ring system including aheterocycle, aryl and carbocycle portion of the ring. It is also to beunderstood that the point of attachment for a heterocycle or heterocyclemultiple condensed ring system can be at any suitable atom of theheterocycle or heterocycle multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). In one embodiment theterm heterocycle includes a C₂₋₂₀ heterocycle. In one embodiment theterm heterocycle includes a C₂₋₇ heterocycle. In one embodiment the termheterocycle includes a C₂₋₅ heterocycle. In one embodiment the termheterocycle includes a C₂₋₄ heterocycle. In one embodiment the termheterocycle includes 3-20 membered heterocycles. In another embodimentthe term heterocycle includes 3-15 membered heterocycles. In anotherembodiment the term heterocycle includes 3-10 membered heterocycles.Exemplary heterocycles include, but are not limited to aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl,benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran,3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine,tropane, 2-azaspiro[3.3]heptane, (1R,5 S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

The term “alkoxy” refers to a linear or branched monovalent radicalrepresented by the formula —OR in which R is alkyl, as defined herein.Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di-and tri-fluoromethoxy and cyclopropoxy.

The term “alkanoyl” refers to group (alkyl)-C(═O)—, wherein alkyl is asdefined herein. For example, C₁-C₆alkanoyl refers to a group of formula(C₁-C₅alkyl)-C(═O)—. Alkanoyl groups include, formyl, acetyl, propanoyl,isopropanoyl, butanoyl, isobutanoyl, pentanoyl, 3-methylpentanoyl, andhexanoyl.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4,or 5 or more, or any range derivable therein) of the substituents listedfor that group in which said substituents may be the same or different.In an embodiment, an optionally substituted group has 1 substituent. Inanother embodiment an optionally substituted group has 2 substituents.In another embodiment an optionally substituted group has 3substituents. In another embodiment an optionally substituted group has4 substituents. In another embodiment an optionally substituted grouphas 5 substituents.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule. In some embodiments, an arrow together withan asterisk is used in the manner of a wavy line to indicate a point ofattachment.

In certain embodiments, divalent groups are described genericallywithout specific bonding configurations. It is understood that thegeneric description is meant to include both bonding configurations,unless specified otherwise. For example, in the group R¹-R²-R³, if thegroup R² is described as —CH₂C(O)—, then it is understood that thisgroup can be bonded both as R¹—CH₂C(O)—R³, and as R¹—C(O)CH₂—R³, unlessspecified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that do not produce an adverse, allergic or otheruntoward reaction when administered to an animal, such as, for example,a human, as appropriate.

Compounds of the invention may be in the form of a salt, such as apharmaceutically acceptable salt. “Pharmaceutically acceptable salts”include both acid and base addition salts. “Pharmaceutically acceptableacid addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free bases and which are notbiologically or otherwise undesirable, formed with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,carbonic acid, phosphoric acid and the like, and organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic, and sulfonic classes of organic acids such asformic acid, acetic acid, propionic acid, glycolic acid, gluconic acid,lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid,maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid,aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoicacid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particular base addition salts are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethyl aminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particular organicnon-toxic bases include isopropylamine, diethylamine, ethanolamine,tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride,hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate,maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate,methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate,ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate,saccharinate, adipate, formate, glycolate, palmitate, L-lactate,D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate(e.g., 2-furoate or 3-furoate), napadisylate(naphthalene-1,5-disulfonate or naphthalene-1-(sulfonicacid)-5-sulfonate), edisylate (ethane-1,2-disulfonate orethane-1-(sulfonic acid)-2-sulfonate), isethionate(2-hydroxyethylsulfonate), 2-mesitylenesulphonate,2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate,L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate(2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate(camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acidsalt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate),orotate, xylate (p-xylene-2-sulphonate), and pamoic(2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all livingmicroorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemicalconstitution, but differ with regard to the arrangement of the atoms orgroups in space. Stereoisomers include diastereomers, enantiomers,conformers and the like.

“Chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g., melting points,boiling points, spectral properties or biological activities. Mixturesof diastereomers may separate under high resolution analyticalprocedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. Many organic compounds exist in optically active forms,i.e., they have the ability to rotate the plane of plane-polarizedlight. In describing an optically active compound, the prefixes D and L,or R and S, are used to denote the absolute configuration of themolecule about its chiral center(s). The prefixes d and 1 or (+) and (−)are employed to designate the sign of rotation of plane-polarized lightby the compound, with (−) or 1 meaning that the compound islevorotatory. A compound prefixed with (+) or d is dextrorotatory. For agiven chemical structure, these stereoisomers are identical except thatthey are mirror images of one another. A specific stereoisomer may alsobe referred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric mixture. A 50:50 mixture of enantiomers isreferred to as a racemic mixture or a racemate, which may occur wherethere has been no stereoselection or stereospecificity in a chemicalreaction or process. The terms “racemic mixture” and “racemate” refer toan equimolar mixture of two enantiomeric species, devoid of opticalactivity.

The term “tautomer” or “tautomeric form” refers to structural isomers ofdifferent energies which are interconvertible via a low energy barrier.For example, proton tautomers (also known as prototropic tautomers)include interconversions via migration of a proton, such as keto-enoland imine-enamine isomerizations. Valence tautomers includeinterconversions by reorganization of some of the bonding electrons.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. A “solvate” refers to anassociation or complex of one or more solvent molecules and a compoundof the present invention. Examples of solvents that form solvatesinclude water, isopropanol, ethanol, methanol, DMSO, ethyl acetate,acetic acid, and ethanolamine. Certain compounds of the invention canexist in multiple crystalline or amorphous forms. In general, allphysical forms are intended to be within the scope of the presentinvention. The term “hydrate” refers to the complex where the solventmolecule is water.

A “metabolite” refers to a product produced through metabolism in thebody of a specified compound or salt thereof. Such products can result,for example, from the oxidation, reduction, hydrolysis, amidation,deamidation, esterification, deesterification, enzymatic cleavage, andthe like, of the administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it in a detectable dose (e.g., greater than about 0.5mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to ahuman, allowing sufficient time for metabolism to occur (typically about30 seconds to 30 hours) and isolating its conversion products from theurine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of thegroups commonly employed to block or protect an amino group whilereactions are carried out on other functional groups on the compound.Examples of such protecting groups include carbamates, amides, alkyl andaryl groups, and imines, as well as many N-heteroatom derivatives whichcan be removed to regenerate the desired amine group. Particular aminoprotecting groups are Pmb (p-Methoxybenzyl), Boc(tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz(Carbobenzyloxy). Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected amino”refers to an amino group substituted with one of the aboveamino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups thatare stable to the conditions of subsequent reaction(s) at otherpositions of the molecule, which may be removed at the appropriate pointwithout disrupting the remainder of the molecule, to give theunprotected carboxy-group. Examples of carboxy protecting groupsinclude, ester groups and heterocyclyl groups. Ester derivatives of thecarboxylic acid group may be employed to block or protect the carboxylicacid group while reactions are carried out on other functional groups onthe compound. Examples of such ester groups include substitutedarylalkyl, including substituted benzyls, such as 4-nitrobenzyl,4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl,2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl,3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl,2,2′,4,4′-tetramethoxybenzhydryl, alkyl or substituted alkyl esters suchas methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl),4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl,2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esterssuch as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl,2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl,beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl,4-nitrobenzyl sulfonylethyl, allyl, cinnamyl,1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Anotherexample of carboxy-protecting groups are heterocyclyl groups such as1,3-oxazolinyl. Further examples of these groups are found in T. W.Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis,3^(rd) ed., John Wiley & Sons, Inc., 1999. The term “protected carboxy”refers to a carboxy group substituted with one of the abovecarboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of thehydroxy group commonly employed to block or protect the hydroxy groupwhile reactions are carried out on other functional groups on thecompound. Examples of such protecting groups includetetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, andsilylethers (e.g., TBS, TBDPS) groups. Further examples of these groupsare found in T. W. Greene and P. G. M. Wuts, “Protecting Groups inOrganic Synthesis, 3^(rd) ed., John Wiley & Sons, Inc., 1999. The term“protected hydroxy” refers to a hydroxy group substituted with one ofthe above hydroxy-protecting groups.

Compounds of the invention may contain one or more asymmetric carbonatoms. Accordingly, the compounds may exist as diastereomers,enantiomers or mixtures thereof. The syntheses of the compounds mayemploy racemates, diastereomers or enantiomers as starting materials oras intermediates. Mixtures of particular diastereomeric compounds may beseparated, or enriched in one or more particular diastereomers, bychromatographic or crystallization methods. Similarly, enantiomericmixtures may be separated, or enantiomerically enriched, using the sametechniques or others known in the art. Each of the asymmetric carbon ornitrogen atoms may be in the R or S configuration and both of theseconfigurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined. Unless otherwise specified, if solid wedges ordashed lines are used, relative stereochemistry is intended. In someinstances, the stereochemistry has not been determined or has beenprovisionally assigned.

Another aspect includes prodrugs of the compounds of the inventionincluding known amino-protecting and carboxy-protecting groups which arereleased, for example hydrolyzed, to yield the compound of the presentinvention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of apharmaceutically active substance that is less efficacious to thepatient compared to the parent drug and is capable of beingenzymatically or hydrolytically activated or converted into the moreactive parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy”Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast(1986) and Stella et al., “Prodrugs: A Chemical Approach to TargetedDrug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp.247-267, Humana Press (1985). Prodrugs include, but are not limited to,phosphate-containing prodrugs, thiophosphate-containing prodrugs,sulfate-containing prodrugs, peptide-containing prodrugs, D-aminoacid-modified prodrugs, glycosylated prodrugs, β-lactam-containingprodrugs, optionally substituted phenoxyacetamide-containing prodrugs oroptionally substituted phenylacetamide-containing prodrugs, and5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom inan amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidinogroup is substituted with a hydroxy group, an alkylcarbonyl (—CO—R)group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl(—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, forexample alkyl, alkylene or aryl, or a group having the Formula—C(O)—O-CP1P2-haloalkyl, where P1 and P2 are the same or different andare hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In aparticular embodiment, the nitrogen atom is one of the nitrogen atoms ofthe amidino group of the compounds of the invention. Prodrugs may beprepared by reacting a compound of the present invention with anactivated group, such as acyl groups, to bond, for example, a nitrogenatom in the compound to the exemplary carbonyl of the activated acylgroup. Examples of activated carbonyl compounds are those containing aleaving group bonded to the carbonyl group, and include, for example,acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acylphenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl,fluorophenoxy acyl, and difluorophenoxy acyl. The reactions aregenerally carried out in inert solvents at reduced temperatures such as−78 to about 50° C. The reactions may also be carried out in thepresence of an inorganic base, for example potassium carbonate or sodiumbicarbonate, or an organic base such as an amine, including pyridine,trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of the inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁. C₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

“Leaving group” refers to a portion of a first reactant in a chemicalreaction that is displaced from the first reactant in the chemicalreaction. Examples of leaving groups include, but are not limited to,halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groupsinclude, but are not limited to, alkylsulfonyloxy groups (for examplemethyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy(triflate group)) and arylsulfonyloxy groups (for examplep-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylategroup)).

A “subject,” “individual,” or “patient” is a vertebrate. In certainembodiments, the vertebrate is a mammal. Mammals include, but are notlimited to, farm animals (such as cows), sport animals, pets (such asguinea pigs, cats, dogs, rabbits and horses), primates, mice and rats.In certain embodiments, a mammal is a human. In embodiments comprisingadministration of a compound of to a patient, the patient is typicallyin need thereof.

The term “Janus kinase” refers to JAK1, JAK2, JAK3 and TYK2 proteinkinases. In some embodiments, a Janus kinase may be further defined asone of JAK1, JAK2, JAK3 or TYK2. In any embodiment, any one of JAK1,JAK2, JAK3 and TYK2 may be specifically excluded as a Janus kinase. Insome embodiments, a Janus kinase is JAK1. In some embodiments, a Januskinase is a combination of JAK1 and JAK2.

The terms “inhibiting” and “reducing,” or any variation of these terms,includes any measurable decrease or complete inhibition to achieve adesired result. For example, there may be a decrease of about, at mostabout, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or anyrange derivable therein, reduction of activity (e.g., JAK1 activity)compared to normal.

In some embodiments, a compound of Formula (I) is selective forinhibition of JAK1 over JAK3 and TYK2. In some embodiments, a compoundof Formula (I) is selective for inhibition of JAK1 over JAK2, JAK3, orTYK2, or any combination of JAK2, JAK3, or TYK2. In some embodiments, acompound of Formula (I) is selective for inhibition of JAK1 and JAK2over JAK3 and TYK2. In some embodiments, a compound of Formula (I) isselective for inhibition of JAK1 over JAK3. By “selective forinhibition” it is meant that the compound is at least a 5%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 99%, or more, or any range derivable therein, better inhibitorof a particular Janus kinase (e.g., JAK1) activity compared to anotherparticular Janus kinase (e.g., JAK3) activity, or is at least a 2-, 3-,4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better inhibitor of aparticular Janus kinase (e.g., JAK1) activity compared to anotherparticular Janus kinase (e.g., JAK3) activity.

“Therapeutically effective amount” means an amount of a compound of thepresent invention, such as a compound of Formula (I), that (i) treats orprevents the particular disease, condition or disorder, or (ii)attenuates, ameliorates or eliminates one or more symptoms of theparticular disease, condition, or disorder, and optionally (iii)prevents or delays the onset of one or more symptoms of the particulardisease, condition or disorder described herein. In some embodiments,the therapeutically effective amount is an amount sufficient to decreaseor alleviate the symptoms of an autoimmune or inflammatory disease(e.g., asthma). In some embodiments, a therapeutically effective amountis an amount of a chemical entity described herein sufficient tosignificantly decrease the activity or number of B-cells. In the case ofcancer, the therapeutically effective amount of the drug may reduce thenumber of cancer cells; reduce the tumor size; inhibit (i.e., slow tosome extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., slow to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; orrelieve to some extent one or more of the symptoms associated with thecancer. To the extent the drug may prevent growth or kill existingcancer cells, it may be cytostatic or cytotoxic. For cancer therapy,efficacy can, for example, be measured by assessing the time to diseaseprogression (TTP) or determining the response rate (RR).

“Treatment” (and variations such as “treat” or “treating”) refers toclinical intervention in an attempt to alter the natural course of theindividual or cell being treated, and can be performed either forprophylaxis or during the course of clinical pathology. Desirableeffects of treatment include preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishment of any direct or indirectpathological consequences of the disease, stabilized (i.e., notworsening) state of disease, decreasing the rate of disease progression,amelioration or palliation of the disease state, prolonging survival ascompared to expected survival if not receiving treatment and remissionor improved prognosis. In some embodiments, compounds of the invention,are used to delay development of a disease or disorder or to slow theprogression of a disease or disorder. Those in need of treatment includethose already with the condition or disorder as well as those prone tohave the condition or disorder, (for example, through a geneticmutation) or those in which the condition or disorder is to beprevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome inwhich an excessive or unregulated inflammatory response leads toexcessive inflammatory symptoms, host tissue damage, or loss of tissuefunction. “Inflammatory disorder” also refers to a pathological statemediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited byinjury or destruction of tissues, which serves to destroy, dilute, orwall off (sequester) both the injurious agent and the injured tissue.Inflammation is notably associated with influx of leukocytes orneutrophil chemotaxis. Inflammation can result from infection withpathogenic organisms and viruses and from noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune responses. Accordingly,inflammatory disorders amenable to treatment with a compound of thepresent invention, such as a compound of Formula (I), encompassdisorders associated with reactions of the specific defense system aswell as with reactions of the nonspecific defense system.

“Specific defense system” refers to the component of the immune systemthat reacts to the presence of specific antigens. Examples ofinflammation resulting from a response of the specific defense systeminclude the classical response to foreign antigens, autoimmune diseases,and delayed type hypersensitivity responses mediated by T-cells. Chronicinflammatory diseases, the rejection of solid transplanted tissue andorgans, e.g., kidney and bone marrow transplants, and graft versus hostdisease (GVHD), are further examples of inflammatory reactions of thespecific defense system.

The term “nonspecific defense system” refers to inflammatory disordersthat are mediated by leukocytes that are incapable of immunologicalmemory (e.g., granulocytes, and macrophages). Examples of inflammationthat result, at least in part, from a reaction of the nonspecificdefense system include inflammation associated with conditions such asadult (acute) respiratory distress syndrome (ARDS) or multiple organinjury syndromes; reperfusion injury; acute glomerulonephritis; reactivearthritis; dermatoses with acute inflammatory components; acute purulentmeningitis or other central nervous system inflammatory disorders suchas stroke; thermal injury; inflammatory bowel disease; granulocytetransfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissueinjury is associated with humoral or cell-mediated responses to thebody's own constituents. Non-limiting examples of autoimmune diseasesinclude rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage,or loss of tissue function resulting from allergy. “Arthritic disease”as used herein refers to any disease that is characterized byinflammatory lesions of the joints attributable to a variety ofetiologies. “Dermatitis” as used herein refers to any of a large familyof diseases of the skin that are characterized by inflammation of theskin attributable to a variety of etiologies. “Transplant rejection” asused herein refers to any immune reaction directed against graftedtissue, such as organs or cells (e.g., bone marrow), characterized by aloss of function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia. The therapeutic methods of thepresent invention include methods for the treatment of disordersassociated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus(including, but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including, but not limited to,major histocompatability antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclearleukocytes such as neutrophils, basophils, and eosinophils), mast cells,dendritic cells, Langerhans cells, and endothelial cells). It will beappreciated by persons skilled in the art that the activation of one ora combination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treatedaccording to the methods of this invention include, but are not limitedto, asthma, rhinitis (e.g., allergic rhinitis), allergic airwaysyndrome, atopic dermatitis, bronchitis, rheumatoid arthritis,psoriasis, contact dermatitis, chronic obstructive pulmonary disease anddelayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and relatedterms refer to or describe the physiological condition in mammals thatis typically characterized by unregulated cell growth. A “tumor”comprises one or more cancerous cells. Examples of cancer includecarcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma,leukemia, and myeloid or lymphoid malignancies. More particular examplesof such cancers include squamous cell cancer (e.g., epithelial squamouscell cancer) and lung cancer including small-cell lung cancer, non-smallcell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamouscarcinoma of the lung. Other cancers include skin, keratoacanthoma,follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx(oral), lip, tongue, mouth, salivary gland, esophageal, larynx,hepatocellular, gastric, stomach, gastrointestinal, small intestine,large intestine, pancreatic, cervical, ovarian, liver, bladder,hepatoma, breast, colon, rectal, colorectal, genitourinary, biliarypassage, thyroid, papillary, hepatic, endometrial, uterine, salivarygland, kidney or renal, prostate, testis, vulval, peritoneum, anal,penile, bone, multiple myeloma, B-cell lymphoma, central nervous system,brain, head and neck, Hodgkin's, and associated metastases. Examples ofneoplastic disorders include myeloproliferative disorders, such aspolycythemia vera, essential thrombocytosis, myelofibrosis, such asprimary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of agiven disorder, for example, cancer or inflammatory disorders. Examplesof chemotherapeutic agents are well-known in the art and includeexamples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. Additionally, chemotherapeutic agentsinclude pharmaceutically acceptable salts, acids or derivatives of anyof chemotherapeutic agents, as well as combinations of two or more ofthem.

“Package insert” is used to refer to instructions customarily includedin commercial packages of therapeutic products that contain informationabout the indications, usage, dosage, administration, contraindicationsor warnings concerning the use of such therapeutic products.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the invention, include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl ¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds(e.g., those labeled with ³H and ¹⁴C) can be useful in compound orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can be useful for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). In some embodiments, in compounds of theinvention, one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enrichedcarbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F areuseful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes or in the Examples herein, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

It is specifically contemplated that any limitation discussed withrespect to one embodiment of the invention may apply to any otherembodiment of the invention. Furthermore, any compound or composition ofthe invention may be used in any method of the invention, and any methodof the invention may be used to produce or to utilize any compound orcomposition of the invention.

The use of the term “or” is used to mean “and/or” unless explicitlyindicated to refer to alternatives only or the alternative are mutuallyexclusive, although the disclosure supports a definition that refers toonly alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that avalue includes the standard deviation of error for the device or methodbeing employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicatedotherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

Inhibitors of Janus Kinases

In one embodiment, the invention provides a compound of Formula (I) asan inhibitor of a Janus kinase (e.g., JAK1):

or a salt thereof, wherein:

R¹ and R^(1a) taken together with the atom to which they are attachedform a 3-10 membered carbocycle optionally substituted with R^(a) andoptionally substituted with R^(b); or R¹ and R^(1a) taken together withthe atom to which they are attached form a 3-10 membered heterocycleoptionally substituted with R and optionally substituted with R^(d);

R² is —NR^(e)R^(f);

R³ is —CH₃ or —CN;

R^(a) is —NR^(r)R^(s);

each R^(b) is independently selected from the group consisting of halo,cyano, hydroxy, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, —NH₂, —NHCH₃, —N(CH₃)₂,—SH, and —SCH₃, wherein any C₁-C₆alkyl, and C₁-C₆alkoxy is optionallysubstituted with halo, cyano, hydroxy, oxo, C₁₋₃alkyl, C₁₋₃alkoxy, —NH₂,—NHCH₃, —N(CH₃)₂, —SH, or —SCH₃, wherein any C₁₋₃alkyl and C₁₋₃alkoxy isoptionally substituted with halo, hydroxy, cyano or oxo;

R^(c) is —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 3-10membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or5-10 membered heteroaryl, wherein any C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl of R^(c) is optionally substituted with R^(x);

each R^(d) is independently selected from the group consisting of halo,cyano, C₁-C₆alkyl, and C₁-C₆alkoxy, wherein any C₁-C₆alkyl, andC₁-C₆alkoxy is optionally substituted with halo, hydroxy, cyano or oxo;

R^(e) is H or C₁-C₄alkyl;

R^(f) is —C(═O)—R^(g), wherein R^(g) is H, hydroxy, C₁-C₆alkyl,C₁-C₆alkoxy, —NR^(t)R^(u), or a 3-10 membered carbocyclyl that isoptionally substituted with halo, hydroxy, cyano, oxo, C₁-C₃alkyl or 3-5membered carbocyclyl;

R^(m) and R^(n) are independently selected from the group consisting ofhydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl, and C₁-C₆alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl, and C₁-C₆alkyl of R^(m) and R^(n) isoptionally substituted with R^(w); or R^(m) and R^(n) are taken togetherwith the atom to which they are attached to form a 3-8 memberedheterocyclyl that is optionally substituted with R^(w);

each R^(r) and R^(s) is independently selected from the group consistingof hydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl and C₁-C₃alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl and C₁-C₃alkyl of R^(r) and R^(s) is optionallysubstituted with R^(v); or R^(r) and R^(s) are taken together with theatom to which they are attached to form a 3-8 membered heterocyclyl or5-10 membered heteroaryl, which 3-8 membered heterocyclyl and 5-10membered heteroaryl is optionally substituted with R^(v);

R^(t) and R^(u) are independently selected from the group consisting ofhydrogen, 3-6 membered heterocyclyl, 3-6 membered carbocyclyl, 6-10membered aryl, 5-10 membered heteroaryl and C₁-C₃alkyl, wherein any 3-6membered heterocyclyl, 3-6 membered carbocyclyl, 6-10 membered aryl,5-10 membered heteroaryl and C₁-C₃alkyl of R^(t) and R^(u) is optionallysubstituted with halo, hydroxy, cyano or oxo; or R^(t) and R^(u) aretaken together with the atom to which they are attached to form a 3-6membered heterocyclyl, optionally substituted with halo, hydroxy, cyanoor oxo, or C₁-C₆alkyl that is optionally substituted with halo, hydroxy,cyano or oxo;

each R^(v) is independently selected from the group consisting of halo,hydroxy, cyano, oxo, 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy of R^(v) is optionally substituted with halo, hydroxy,cyano, C₁-C₆alkyl, oxo, 3-6 membered carbocycle, 3-6 memberedheterocyclyl, C₁-C₆alkoxy, 5-10 membered heteroaryl or 6-10 memberedaryl, each of which is optionally substituted with halo, hydroxy, cyano,oxo C₁-C₃alkyl or C₁-C₃alkoxy;

each R^(w) is independently selected from the group consisting of halo,hydroxy, cyano, oxo, 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl andC₁-C₆alkoxy of R^(w) is optionally substituted with halo, hydroxy,cyano, C₁-C₆alkyl, oxo, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl C₁-C₆alkoxy, 5-10 membered heteroaryl, or 6-10 memberedaryl, each optionally substituted with halo, hydroxy, cyano, oxo,C₁-C₃alkyl or C₁-C₃alkoxy; and

each R^(x) is independently selected from the group consisting of halo,hydroxy, cyano, nitro, oxo, —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m),—C(O)OR^(m), —C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m),—NR^(m)S(O)₁₋₂R^(n), —S(O)₁₋₂NR^(m)R^(n), 3-10 membered carbocyclyl,3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 memberedheteroaryl, wherein any 3-10 membered carbocyclyl, 3-10 memberedheterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, isoptionally substituted with halo, hydroxy, cyano, nitro, C₂-C₃ alkynyl,—OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, oxo, 3-10 membered carbocyclyl, 3-10membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl,wherein any C₁-C₆alkyl, C₂-C₃ alkynyl, 3-10 membered carbocyclyl, 3-10membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroarylis optionally substituted with halo, hydroxy, cyano, oxo, —OR^(m),—NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n), 3-6 memberedcarbocyclyl, 6-10 membered aryl, or C₁-C₆alkyl that is optionallysubstituted with halo, hydroxy, cyano, oxo or C₁-C₆alkoxy.

In some embodiments, R^(g) is H, C₁-C₆alkyl, C₁-C₆alkoxy, —NR^(t)R^(u),or a 3-10 membered carbocyclyl that is optionally substituted with halo,hydroxy, cyano, oxo, C₁-C₃alkyl or 3-5 membered carbocyclyl

In some embodiments, each R^(x) is independently selected from the groupconsisting of halo, hydroxy, cyano, nitro, oxo, —OR^(m), —SR^(m),—NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n),—NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), 3-10 membered carbocyclyl, 3-10 memberedheterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl, whereinany 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 memberedaryl, and 5-10 membered heteroaryl, is optionally substituted with halo,hydroxy, cyano, nitro, —OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m),—C(O)OR^(m), —C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m),—NR^(m)S(O)₁₋₂R^(n), —S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, oxo, 3-10 memberedcarbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10membered heteroaryl, wherein any C₁-C₆alkyl, 3-10 membered carbocyclyl,3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 memberedheteroaryl is optionally substituted with halo, hydroxy, cyano, oxo,—OR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n), 6-10membered aryl, or C₁-C₆alkyl that is optionally substituted with halo,hydroxy, cyano, oxo or C₁-C₆alkoxy.

In some embodiments, R³ is —CH₃.

In some embodiments, R³ is —CN.

In some embodiments, a compound of Formula (I) is further defined as acompound of Formula (Ia):

or a salt thereof.

In some embodiments, a compound of Formula (I) is further defined as acompound of Formula (Ib):

In some embodiments, a compound of Formula (I) is further defined as acompound of Formula (Ic):

or a salt thereof.

In some embodiments, a compound of Formula (I) is further defined as acompound of Formula (Id):

or a salt thereof.

In some embodiments, R² is selected from the group consisting of:

In some embodiments, R² is selected from the group consisting of:

In some embodiments, R² is cyclopropylcarbonylamino.

In some embodiments, the group

is selected from the group consisting of:

and optionally may further include

In some embodiments, the group

is selected from the group consisting of:

In some embodiments, the group

is selected from the group consisting of:

In some embodiments, the group

is selected from the group consisting of:

In some embodiments, the group

is selected from the group consisting of:

In some embodiments, R^(a) is selected from the group consisting of:

In some embodiments, R^(a) is selected from the group consisting of:

In some embodiments, R^(c) is C₁-C₆alkyl that is substituted with R^(x);and R^(x) is selected from the group consisting of 3-10 memberedcarbocyclyl, 3-10 membered heterocycle, 6-10 membered aryl, and 5-10membered heteroaryl, wherein any 3-10 membered carbocyclyl, 3-10membered heterocycle, 6-10 membered aryl, and 5-10 membered heteroarylis optionally substituted with 3-10 membered carbocyclyl, 3-10 memberedheterocycle, 6-10 membered aryl, or 5-10 membered heteroaryl, whereinany 3-10 membered carbocyclyl, 3-10 membered heterocycle, 6-10 memberedaryl, and 5-10 membered heteroaryl is optionally substituted with halo,hydroxy, cyano, oxo, —OR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), or C₁-C₆alkyl that is optionally substituted withhalo, hydroxy, cyano, oxo or C₁-C₆alkoxy.

In some embodiments, R^(c) is selected from the group consisting of:

In some embodiments, R^(c) is selected from the group consisting of:

In some embodiments, a compound of the invention is selected from thegroup consisting of:

and salts thereof.

In some embodiments, a compound of the invention is selected from thegroup consisting of:

and salts thereof.

In some embodiments, a compound of the invention is selected from thegroup consisting of:

and salts thereof.

In some embodiments, a compound of the invention is selected from thegroup consisting of:

and salts thereof.

In some embodiments, the group

is selected from the group consisting of:

In some embodiments, R^(a) is selected from the group consisting of:

In some embodiments, R^(c) is selected from the group consisting of:

Also provided is a compound selected from Examples 1-304, and saltsthereof.

Also provided is a compound selected from Table 1 below, or anycombination thereof, and any salt thereof.

TABLE 1 Exemplary Compounds of the Present Invention Ex. Structure Name1, 2

1-[1-(cyanomethyl)-4-(2,2,2- trifluoroethylamino) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide

3

1-[1-(cyanomethyl)-4-(2,2,2- trifluoroethylamino) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 4

1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)- 4-piperidyl]-3-(methylcarbamoylamino) pyrazole-4-carboxamide 5

methyl N-[4-carbamoyl- 1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)-4-piperidyl]pyrazol-3-yl] carbamate 6

1-[7-(cyanomethyl)- 2-oxaspiro[3.5]nonan- 7-yl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 7, 8

1-[4-(cyanomethyl)-1- [(4-phenylphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide

9, 10

1-[4-(cyanomethyl)-4- [3-(trifluoromethyl) azetidin-1-yl]cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide

11

1-[1-(cyanomethyl)-4- [3-(trifluoromethyl) azetidin-1-yl]cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 12, 13, 14, 15

1-[1-(cyanomethyl)-4- [3-ethoxy-3- (trifluoromethyl)azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide

16

1-[1-(cyanomethyl)-4- [3-ethoxy-3- (trifluoromethyl)azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide17

1-[4-(cyanomethyl)-1- [(3-hydroxy-4-phenyl- phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 18

1-[4-(cyanomethyl)-3- fluoro-1-[(4-phenylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 19, 20

1-[4-(cyanomethyl)-3- fluoro-1-[(4-phenylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide

21

1-[4-(cyanomethyl)-3- fluoro-1-[(4-phenylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 22

1-[4-(cyanomethyl)-3- fluoro-1-[(4-phenylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 23

1-[1-[[6-(5-chloro-3- thienyl)-3-pyridyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 24

cyclopropylmethyl 4- [4-carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4-(cyanomethyl) piperidine-1-carboxylate 25

1-[4-(cyanomethyl)-1- (2-phenylacetyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 26

1-[4-(cyanomethyl)-1-(2- hydroxy-1-phenyl-ethyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 27

1-[4-(cyanomethyl)-1-(2- hydroxy-2-phenyl-ethyl)- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 28

4-[4-carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4-(cyanomethyl)- N-(3,3-difluorocyclobutyl)piperidine-1-carboxamide 29

1-[4-(cyanomethyl)-1-(1- phenylethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 30

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 31

3-acetamido-1-[4- (cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]pyrazole-4-carboxamide 32

1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)-4- piperidyl]-3-(spiro[2.2]pentane-2- carbonylamino)pyrazole- 4-carboxamide 33

1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)-4- piperidyl]-3-[(2,2-difluorocyclopropanecarbonyl) amino]pyrazole-4- carboxamide 34

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-[[rac-(1R,2R)-2- (trifluoromethyl) cyclopropanecarbonyl]amino]pyrazole-4- carboxamide 35

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-[[rac-(1S,2S)-2- fluorocyclopropanecarbonyl]amino]pyrazole-4-carboxamide 36

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-[[rac-(1R,2R)-2- fluorocyclopropanecarbonyl]amino]pyrazole-4-carboxamide 37

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-[[rac-(1S,2R)-2- fluorocyclopropanecarbonyl]amino]pyrazole-4-carboxamide 38

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-(spiro[2.3]hexane-2- carbonylamino)pyrazole- 4-carboxamide 39

1-[4-(cyanomethyl)-1-(2,2,2- trifluoroethyl)-4-piperidyl]-3-[[rac-(1R,2R)-2- methylcyclopropanecarbonyl] amino]pyrazole-4-carboxamide 40

1-[1-(cyanomethyl)cyclohexyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 41

1-[1′-(cyanomethyl)spiro [1,3-benzodioxole-2,4′- cyclohexane]-1′-yl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 42

tert-butyl N-[4-[4-carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4-(cyanomethyl) cyclohexyl]carbamate 43

tert-butyl N-[4-[4- carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4-(cyanomethyl) cyclohexyl]carbamate 44

1-[4-(cyanomethyl)-1- [(3-phenylphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 45

1-[4-(cyanomethyl)-1- [(2-phenylphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 46

1-[4-(cyanomethyl)-1- [[4-(1-piperidyl)phenyl] methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 47

1-[1-benzyl-4- (cyanomethyl)-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 48

1-[4-(cyanomethyl)-1- [(2-methoxyphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 49

1-[4-(cyanomethyl)-1- [(3-methoxyphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 50

1-[4-(cyanomethyl)-1- [(4-methoxyphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 51

1-[4-(cyanomethyl)-1- [[2-(methanesulfonamido)phenyl]methyl]-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 52

1-[4-(cyanomethyl)-1- [[3-(methanesulfonamido)phenylmethyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 53

1-[4-(cyanomethyl)-1-[[4- (methanesulfonamido)phenyl]methyl]-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 54

1-[4-(cyanomethyl)-1- [[2-(trifluoromethoxy)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 55

1-[4-(cyanomethyl)-1- [[3-(trifluoromethoxy)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 56

1-[4-(cyanomethyl)-1- [[4-(trifluoromethoxy)phenyl]methyl]-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 57

1-[1-[(2-bromophenyl)methyl]- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 58

1-[1-[(3-bromophenyl)methyl]- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 59

1-[1-[(4-bromophenyl)methyl]- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 60

1-[4-(cyanomethyl)-1-[(2- iodophenyl)methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 61

1-[4-(cyanomethyl)-1- [(3-iodophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 62

1-[4-(cyanomethyl)-1- [(4-iodophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 63

1-[4-(cyanomethyl)-1- [(3-fluorophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 64

1-[4-(cyanomethyl)-1- [(4-fluorophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 65

1-[1-[(2-chlorophenyl)methyl]- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 66

1-[1-[(3-chlorophenyl) methyl]- 4-(cyanomethyl)- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 67

1-[1-[(4-chlorophenyl) methyl]-4-(cyanomethyl)- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 68

1-[4-(cyanomethyl)-1- [[2-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 69

1-[4-(cyanomethyl)-1- [[3-(trifluoromethyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 70

1-[4-(cyanomethyl)-1- [[4-(trifluoromethyl)phenylmethyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 71

1-[4-(cyanomethyl)-1- [(2-cyanophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 72

1-[4-(cyanomethyl)-1- [(3-cyanophenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 73

1-[4-(cyanomethyl)-1- [(4-cyanophenyl)methyl]- 4-piperidyl]-3-cyclopropanecarbonylamino) pyrazole-4-carboxamide 74

1-[4-(cyanomethyl)-1- [[3-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 75

1-[4-(cyanomethyl)-1- [[4-(trifluoromethylsulfanyl)phenyl]methyl]-4-piperidyl]- 3-(cyclopropanecarbonylamino)pyrazole-4-carboxamide 76

1-[4-(cyanomethyl)-1- [(2-methylsulfonylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 77

1-[4-(cyanomethyl)-1- [(3-methylsulfonylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 78

1-[4-(cyanomethyl)-1- [(4-methylsulfonylphenyl) methyl]-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 79

1-[4-(cyanomethyl)-1- (1H-indol-6-ylmethyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide; formic acid 80

1-[1-(3H-benzimidazol-5- ylmethyl)-4-(cyanomethyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 81

1-[1-[[3- (benzenesulfonamido)phenyl] methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 82

1-[4-(cyanomethyl)-1-[[3- (ethylsulfonylamino)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide; formic acid 83

1-[1-[(3- acetamidophenyl)methyl]-4- (cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 84

1-[1-[(4-bromo-3-fluoro- phenyl)methyl]-4- (cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 85

1-[4-(cyanomethyl)-1-[[2- fluoro-3- (methanesulfonamido)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 86

1-[4-(cyanomethyl)-1-[[4- fluoro-3- (methanesulfonamido)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 87

1-[4-(cyanomethyl)-1-[[3- fluoro-5- (methanesulfonamido)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 88

1-[1-[(3-acetamido-4-chloro- phenyl)methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 89

1-[4-(cyanomethyl)-1-[[4-(1- methylpyrazol-3- yl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 90

1-[4-(cyanomethyl)-1-[[4-[3- (trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 91

1-[4-(cyanomethyl)-1-[(4- pyrrolidin-1-ylphenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 92

1-[4-(cyanomethyl)-1-[(4- imidazol-1-ylphenyl)methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 93

1-[4-(cyanomethyl)-1-[[4- (1,2,4-triazol-1- yl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 94

1-[4-(cyanomethyl)-1-[(4- pyrazol-1-ylphenyl)methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 95

1-[1-[[4-(benzimidazol-1- yl)phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 96

1-[4-(cyanomethyl)-1-[[4- (triazol-2-yl)phenyl]methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 97

1-[4-(cyanomethyl)-1-[(1- phenylpyrazol-4-yl)methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 98

1-[4-(cyanomethyl)-1-(1,3- dihydro-2-benzothiophen-5-ylmethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 99

1-[4-(cyanomethyl)-1-[[3- (difluoromethoxy)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 100

1-[4-(cyanomethyl)-1-[[3- (trifluoromethylsulfonylamino)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 101

1-[4-(cyanomethyl)-1-[[3- (isopropylsulfonylamino)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 102

1-[1-(9H-carbazol-2-ylmethyl)- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 103

1-[4-(cyanomethyl)-1-(3,3,3- trifluoropropyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 104

1-[1-[[3- (aminomethyl)phenyl]methyl]- 4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 105

1-[4-(cyanomethyl)-1-[1-[3- fluoro-2- (trifluoromethyl)pyridine-4-carbonyl]-4-piperidyl]-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 106

1-[1-(cyanomethyl)-4- (methylamino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 107

1-[1-(cyanomethyl)-4- (methylamino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 108

1-[1-(cyanomethyl)-4-(3- methoxyazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 109

1-[1-(cyanomethyl)-4-(3- methoxyazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 110

1-[1-(cyanomethyl)-4- (tetrahydropyran-4- ylamino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 111

1-[1-(cyanomethyl)-4- (tetrahydropyran-4- ylamino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 112

1-[1-(cyanomethyl)-4-(3,3- dimethylazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide; formic acid 113

1-[1-(cyanomethyl)-4-(3,3- dimethylazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 114

1-[4-(2-azaspiro[3.3] heptan-2-yl)-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide; formic acid 115

1-[4-(2-azaspiro[3.3] heptan-2-yl)-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 116

1-[4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide; formic acid 117

1-[4-(benzylamino)-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide; formic acid 118

1-[1-(cyanomethyl)-4-[(2- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 119

1-[1-(cyanomethyl)-4-[(2- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 120

1-[1-(cyanomethyl)-4-[(3- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 121

1-[1-(cyanomethyl)-4-[(3- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 122

1-[1-(cyanomethyl)-4-[(4- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 123

1-[1-(cyanomethyl)-4-((4- fluorophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 124

1-[4-[(2- chlorophenyl)methylamino]-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 125

1-[4-[(2- chlorophenyl)methylamino]-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 126

1-[4-[(4- chlorophenyl)methylamino]-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 127

1-[4-[(4- chlorophenyl)methylamino]-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 128

1-[1-(cyanomethyl)-4-[(4- cyanophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 129

1-[1-(cyanomethyl)-4-[(4- cyanophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 130

1-[1-(cyanomethyl)-4-[(3- cyanophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 131

1-[1-(cyanomethyl)-4-[(3- cyanophenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 132

1-[1-(cyanomethyl)-4-(3,3,3- trifluoropropylamino) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 133

1-[1-(cyanomethyl)-4-(3,3- trifluoropropylamino) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 134

1-[1-(cyanomethyl)-4-[(4- phenylphenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 135

1-[1-(cyanomethyl)-4-[(4- phenylphenyl)methylamino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 136

1-[1-(cyanomethyl)-4- [methyl(2,2,2- trifluoroethyl)amino]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 137

1-[1-(cyanomethyl)-4-[3- hydroxy-3- (trifluoromethyl)azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 138

1[1-(cyanomethyl)-4-[3- hydroxy-3- (trifluoromethyl)azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 139

1-[4-(cyanomethyl)-1-[[4-(3- fluorophenyl)-3-hydroxy-phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 140

1-[4-(cyanomethyl)-1-[(3- fluoro-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 141

1-[1-[[4-(5-chloro-3-thienyl)-3- fluoro-phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 142

1-[4-(cyanomethyl)-1-[[4-(2- fluorophenyl(phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 143

1-[4-(cyanomethyl)-1-[[4-(3- fluorophenyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 144

1-[4-(cyanomethyl)-1-[[4-[2- (dimethylcarbamoyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 145

1-[4-(cyanomethyl)-1-[[4-[3- (dimethylcarbamoyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 146

1-[1-[[4-(3- chlorophenyl)phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 147

1-[1-[[4-(4- chlorophenyl(phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 148

1-[1-[[4-(5-chloro-2- thienyl)phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 149

1-[1-[[4-(5-chloro-3- thienyl)phenyl]methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 150

1-[4-(cyanomethyl)-1-[[4-[3- (trifluoromethyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 151

1-[4-(cyanomethyl)-1-[[4-[4- (trifluoromethyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 152

1-[4-(cyanomethyl)-1-[[4-(3- methoxyphenyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 153

1-[4-(cyanomethyl)-1-[[4-(4- methoxyphenyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 154

1-[4-(cyanomethyl)-1-[[4-(3- ethylphenyl)phenyl]methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 155

1-[4-(cyanomethyl)-1-[[4-(4- ethylphenyl)phenyl]methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 156

1-[4-(cyanomethyl)-1-[[4-[3- (hydroxymethyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 157

1-[4-(cyanomethyl)-1-[[4-[3- (methoxymethyl)phenyl]phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 158

1-[4-(cyanomethyl)-1-[[4-(3- pyridyl)phenyl]methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 159

1-[4-(cyanomethyl)-1-[[4-(4- pyridyl)phenyl]methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 160

1-[4-(cyanomethyl)-1-[(3- methyl-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 161

1-[4-(cyanomethyl)-1-[(3- cyano-4-phenyl-phenyl)methyl]- 4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 162

1-[4-(cyanomethyl)-1-[(3- methoxy-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 163

1-[1-[(3-chloro-4-phenyl- phenyl)methyl]-4-(cyanomethyl)-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 164

1-[1-benzyl-4-(cyanomethyl)-3- fluoro-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 165

tert-butyl 4-[4-carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4-(cyanomethyl)- 3-fluoro-piperidine-1- carboxylate 166

1-[4-(cyanomethyl)-1-[[6-[4- (trifluoromethyl)phenyl]-3-pyridyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 167

2,2,2-trifluoroethyl 4-[4- carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate 168

1-[4-(cyanomethyl)-1-(3,3- difluorocyclobutanecarbonyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 169

1-[4-(cyanomethyl)-1-(4,4,4- trifluorobutanoyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 170

1-[4-(cyanomethyl)-1-(3,3,3- trifluoropropanoyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 171

1-[4-(cyanomethyl)-1-(2,2- difluoropropanoyl)-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 172

1-[1-(cyanomethyl)-4-[(3,3- difluorocyclobutyl)amino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 173

1-[1-(cyanomethyl)-4-[(3,3- difluorocyclobutyl)amino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 174

1-[1-(cyanomethyl)-4-[(4,4- difluorocyclohexyl)amino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 175

1-[1-(cyanomethyl)-4-[(4,4- difluorocyclohexyl)amino] cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 176

1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)-4- piperidyl]-3-[(2-cyclopropylcyclopropanecarbon yl)amino]pyrazole-4- carboxamide 177

1-[4-(cyanomethyl)-1- (2,2,2-trifluoroethyl)-4- piperidyl]-3-[(2-cyclopropylcyclopropanecarbon yl)amino]pyrazole-4- carboxamide 178

1-[1-(cyanomethyl)-4- (3,3-difluoroazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 179

1-[1-(cyanomethyl)-4- (3,3-difluoroazetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 180

1-[1-(cyanomethyl)-4- (3-fluoroazetidin-1-yl) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 181

1-[1-(cyanomethyl)-4- (3-fluoroazetidin-1-yl) cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 182

1-cyclopropylethyl 4-[4- carbamoyl-3- (cyclopropanecarbonylamino)pyrazol-1-yl]-4- (cyanomethyl)piperidine-1- carboxylate 183

1-[4-(cyanomethyl)-1-(2- phenylethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 184

1-[4-(cyanomethyl)-1-[(2- fluorophenyl)methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 185

1-[4-(cyanomethyl)-1-[[4-(2- pyridyl)phenyl]methyl]-4- piperidyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 186

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(3-hydroxy-4-phenyl-phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 187

ethyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(3-hydroxy-4-phenyl-phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 188

1-[4-(cyanomethyl)-1-[(2-fluoro- 6-phenyl-3-pyridyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 189

1-[4-(cyanomethyl)-1-[[4-(4- ethylphenyl)-3-hydroxy-phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 190

1-[4-(cyanomethyl)-1-[[3- fluoro-4-[1-(2,2,2- trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 191

1-[4-(cyanomethyl)-1-[(2-fluoro- 5-hydroxy-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 192

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(4-phenylphenyl) methyl]-4- piperidyl]pyrazole-4- carboxamide193

1-[4-(cyanomethyl)-3-fluoro-1- [(6-phenyl-3-pyridyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 194

1-[4-(cyanomethyl)-1-[(3- hydroxy-2-methyl-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 195

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(3-hydroxy-4-phenyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate196

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(6-phenyl-3-pyridyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate 197

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(triazol-2-yl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl] carbamate 198

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(2-fluoro-6-phenyl-3-pyridyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate 199

1-[4-(cyanomethyl)-3-fluoro-1- [[4-(triazol-2-yl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 200

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(triazol-2-yl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 201

1-[4-(cyanomethyl)-3-fluoro-1- [(2-fluoro-6-phenyl-3-pyridyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 202

1-[4-(cyanomethyl)-1-[(4-fluoro- 6-phenyl-3-pyridyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 203

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-6-phenyl-3- pyridyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate204

1-[4-(cyanomethyl)-1-[(2- hydroxy-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 205

1-[1-(cyanomethyl)-4-(3-fluoro- 3-phenyl-azetidin-1- yl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 206

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(2-fluoro-5-hydroxy-4-phenyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate207

1-[4-(cyanomethyl)-3-fluoro-1- [(2-fluoro-5-hydroxy-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 208

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-5-hydroxy-4-phenyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 209

cyclopropyl N-[4-carbamoyl-1- [4-(cyanomethyl)-1-[(3-hydroxy-4-phenyl-phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 210

1-[1-(cyanomethyl)-4-(4- phenylphenoxy)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 211

1-[1-(cyanomethyl)-4-(4- phenylphenoxy)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 212

1-[4-(cyanomethyl)-1-[[4-(4- ethylphenyl)-3-hydroxy-phenyl]methyl]-3-fluoro-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 213

1-[4-(cyanomethyl)-3-fluoro-1- [(3-hydroxy-2-methyl-4-phenyl-phenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 214

1-[4-(cyanomethyl)-3-fluoro-1- [[4-(3-furyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 215

1-[4-(cyanomethyl)-3-fluoro-1- [[4-(2-furyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 216

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(1- ethylpyrazol-3-yl)phenyl]methyl]-3-fluoro-4- piperidyl]pyrazol-3-yl] carbamate 217

1-[4-(cyanomethyl)-1-[[4-(1- ethylpyrazol-3-yl)phenyl]methyl]-3-fluoro-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 218

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(2-fluoro-4-phenyl- phenyl)methyl]-4- piperidyl]pyrazole-4-carboxamide 219

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(2-fluoro-4-phenyl- phenyl)methyl]-4- piperidyl]pyrazole-4-carboxamide 220

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(2-furyl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl] carbamate 221

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-1-[[4-(4-ethylphenyl)-3-hydroxy- phenyl]methyl]-3-fluoro-4- piperidyl]pyrazole-4-carboxamide 222

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-1-[[4-(4-ethylphenyl)-3-hydroxy- phenyl]methyl]-3-fluoro-4- piperidyl]pyrazole-4-carboxamide 223

1-[4-(cyanomethyl)-3-fluoro-1- [[4-(5-methyl-2- furyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 224

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(2-furyl)-3-hydroxy- phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 225

ethyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(triazol-2-yl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 226

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[2-fluoro-6-(2-furyl)-3- pyridyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 227

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(2-fluoro-6-phenyl-3- pyridyl)methyl]-4-piperidyl]pyrazole-4-carboxamide 228

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(4-phenylcyclohexyl) methyl]-4-piperidyl]pyrazole-4-carboxamide 229

1-[4-(cyanomethyl)-1-[[4- (cyclohexen-1-yl)phenyl] methyl]-3-fluoro-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 230

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(4-phenylcyclohexyl) methyl]-4-piperidyl]pyrazole-4-carboxamide 231

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(4-phenylcyclohexyl) methyl]-4-piperidyl]pyrazole-4-carboxamide 232

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(5-ethyl-2-furyl)phenyl]methyl]-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 233

1-[4-(cyanomethyl)-3-fluoro-1- [(4-phenylcyclohexyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 234

1-[4-(cyanomethyl)-3-fluoro-1- [(4-phenylcyclohexyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 235

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(4-phenylcyclohexyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 236

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(4-phenylcyclohexyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 237

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[2-fluoro-4-(3-furyl)-5-hydroxy- phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 238

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[2-fluoro-4-(2-furyl)-5-hydroxy- phenyl]methyl]-4-piperidyl]pyrazol-3-yl]carbamate 239

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[2-fluoro-6-(3-furyl)-3- pyridyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 240

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(2-fluoro-5-hydroxy- 4-phenyl-phenyl)methyl]-4-piperidyl]pyrazole-4- carboxamide 241

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(1-ethylpyrazol-3-yl)-2-fluoro- phenyl]methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 242

1-[4-(cyanomethyl)-1-[[4-(1- ethylpyrazol-3-yl)-2-fluoro-phenyl]methyl]-3-fluoro-4- piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 243

methyl N-[4-carbamoyl-1-[1- (cyanomethyl)-4-(3-fluoro-3-phenyl-azetidin-1- yl)cyclohexyl]pyrazol-3- yl]carbamate 244

methyl N-[4-carbamoyl-1-[4- (cyanomelhyl)-3-fluoro-1-[[4-(3-furyl)-3-hydroxy- phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate 245

1-[1-(cyanomethyl)-4-(4- phenylanilino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 246

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(5-methyl-2-furyl)phenyl]methyl]- 4-piperidyl]pyrazol-3- yl]carbamate 247

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[3-hydroxy-4-(5-methyl-2- furyl)phenyl]methyl]-4-piperidyl]pyrazol-3-yl]carbamate 248

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(2,6-difluoro-3-hydroxy-4-phenyl- phenyl)methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 249

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(2-methylthiazol-4- yl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate250

3-[(2- cyanocyclopropanecarbonyl) amino]-1-[4-(cyanomethyl)-3-fluoro-1-[(3-hydroxy-2- methyl-4-phenyl-phenyl)methyl]-4-piperidyl]pyrazole-4- carboxamide; formic acid 251

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(4-fluoro-6-phenyl-3- pyridyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate252

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(2- ethylthiazol-4-yl)phenyl]methyl]-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 253

1-[4-(cyanomethyl)-1-[[4-(4- methyltriazol-2-yl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 254

1-[4-(cyanomethyl)-3-fluoro-1- [(4-phenylphenyl)methyl]-4-piperidyl]-3-[(2- ethynylcyclopropanecarbonyl)amino]pyrazole-4-carboxamide 255

1-[4-(cyanomethyl)-3-fluoro-1- [(4-oxazol-2-ylphenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 256

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[2-fluoro-5-hydroxy-4-(5-methyl-2- furyl)phenyl]methyl]-4-piperidyl]pyrazol-3-yl]carbamate 257

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4- (cyclohexen-1-yl)phenyl]methyl]-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 258

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(cyclohexen-1-yl)-3-hydroxy- phenyl]methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 259

1-[4-(cyanomethyl)-3-fluoro-1- [(4-isopropenylphenyl)methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 260

1-[4-(cyanomethyl)-1-[(4- ethynylphenyl)methyl]-3-fluoro-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 261

1-[4-(cyanomethyl)-1-[[4- (cyclopenten-1-yl) phenyl]methyl]-3-fluoro-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 262

methyl N-[4-carbamoyl-1-[1- (cyanomethyl)-4-(4-phenylanilino)cyclohexyl] pyrazol-3-yl]carbamate 263

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-3-hydroxy-4-phenyl- phenyl)methyl]-4-piperidyl]pyrazol-3-yl]carbamate 264

methyl N-[4-carbamoyl-1-[4- (cyanomelhyl)-1-[[6-(cyclohexen-1-yl)-2-fluoro-3- pyridyl]methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 265

1-[1-(cyanomethyl)-4-[3-(4- ethylphenyl)-3-fluoro-azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 266

methyl N-[4-carbamoyl-1-[1- (cyanomethyl)-4-[4-(2-furyl)anilino]cyclohexyl]pyrazol- 3-yl]carbamate 267

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[4-(4-methyltriazol-2- yl)phenyl]methyl]-4- piperidyl]pyrazol-3-yl]carbamate268

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4- (cyclopenten-1-yl)phenyl]methyl]-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 269

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[4-(cyclopenten-1-yl)-3-hydroxy- phenyl]methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 270

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(4-ethynylphenyl)methyl]-3-fluoro- 4-piperidyl]pyrazol-3- yl]carbamate 271

1-[4-(cyanomethyl)-1-[(4- cyclohexylphenyl)methyl]-3-fluoro-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 272

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[6-(cyclopenten-1-yl)-2-fluoro-3- pyridyl]methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl]carbamate 273

methyl N-[4-carbamoyl-1-[1-[(2- chloro-5-hydroxy- phenyl)methyl]-4-(cyanomethyl)-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 274

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-5-hydroxy-4-isopropenyl- phenyl)methyl]-4-piperidyl]pyrazol-3-yl]carbamate 275

1-[1-(cyanomethyl)-4-[4- (cyclopenten-1- yl)anilino]cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 276

1-[1-(cyanomethyl)-4-[4-(2- furyl)anilino]cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 277

1-[4-(cyanomethyl)-1-[[3- hydroxy-4-(triazol-2- yl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 278

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(4-oxazol-2-ylphenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 279

1-[1-(cyanomethyl)-4-(4- ethynylanilino)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 280

1-[1-[(2-chloro-4-ethynyl- phenyl)methyl]-4- (cyanomethyl)-3-fluoro-4-piperidyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 281

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(4-cyclopropylphenyl)methyl]-3- fluoro-4-piperidyl]pyrazol-3- yl]carbamate282

1-[4-anilino-1- (cyanomethyl)cyclohexyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 283

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[[5-(difluoromethyl)-2-fluoro- phenyl)methyl]-3-fluoro-4-piperidyl]pyrazol-3-yl] carbamate 284

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(3-hydroxy-4-vinyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate 285

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-5-hydroxy-4-vinyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 286

1-[4-(cyanomethyl)-3-fluoro-1- [[3-hydroxy-4-(triazol-2-yl(phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamidc 287

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[[3-hydroxy-4-(triazol-2- yl(phenyl]methyl]-4-piperidyl]pyrazol-3-yl]carbamate 288

1-[1-(cyanomethyl)-4-[4-(triazol- 2-yl)anilino]cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 289

methyl N-[4-carbamoyl-1-[1-[(2- chloro-4-ethynyl- phenyl)methyl]-4-(cyanomethyl)-3-fluoro-4- piperidyl]pyrazol-3-yl]carbamate 290

1-[4-(2-chloroanilino)-1- (cyanomethyl)cyclohexyl]-3-(cyclopropanecarbonylamino) pyrazole-4-carboxamide 291

1-[1-(cyanomethyl)-4-[3-(4- (difluoromethoxy)phenoxy]-3-methyl-azetidin-1- yl]cyclohexyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 292

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(2-fluoro-5-hydroxy-4-methyl- phenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 293

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(3-fluoro-5-hydroxy- phenyl)methyl]-4- piperidyl]pyrazol-3-yl] carbamate294

1-[1-(cyanomethyl)-4-[3-(4- ethynylphenoxy)-3-methyl-azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 295

1-[1-(cyanomethyl)-4- [3-methyl-3-[4- (trifluoromethyl)phenoxy]azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 296

methyl N-[1-[1-[(4-bromo-2- chloro-5-hydroxy- phenyl)methyl]-4-(cyanomethyl)-3-fluoro-4- piperidyl]-4-carbamoyl-pyrazol- 3-yl]carbamate297

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-1-[(4-ethynyl-2-fluoro-phenyl)methyl]-3-fluoro- 4-piperidyl]pyrazol-3- yl]carbamate 298

methyl N-[4-carbamoyl-1-[4- (cyanomethyl)-3-fluoro-1-[(4-prop-1-ynylphenyl)methyl]-4- piperidyl]pyrazol-3-yl]carbamate 299

1-[4-(cyanomethyl)-1-[[4-(2- cyclopropylethynyl)phenyl]methyl]-4-piperidyl]-3- (cyclopropanecarbonylamino)pyrazole-4-carboxamide 300

1-[1-(cyanomethyl)-4-[3-methyl- 3-(4-methylphenoxy)azetidin-1-yl]cyclohexyl]-3- (cyclopropanecarbonylamino) pyrazole-4-carboxamide 301

3-[4- (difluoromethylsulfonyl)anilino]- 1-[4-ethyl-1-[(2-fluoro-5-hydroxy-phenyl)methyl]-4- piperidyl]pyrazole-4- carboxamide 302

1-[1-ethyl-4-[3- (trifluoromethyl)azetidin-1- yl]cyclohexyl]-3-(4-methylsulfonylanilino) pyrazole-4-carboxamide 303

1-[1-(cyanomethyl)-4-[3- (trifluoromethyl)azetidin-1-yl]cyclohexyl]-3-(4- diethoxyphosphorylanilino) pyrazole-4-carboxamide304

1-[1-(2-cyanoacetyl)-4-ethyl-4- piperidyl]-3-[4-(difluoromethylsulfonyl)anilino] pyrazole-4-carboxamide

In one embodiment the disease or condition is cancer, polycythemia vera,essential thrombocytosis, myelofibrosis, chronic myelogenous leukemia(CML), rheumatoid arthritis, inflammatory bowel syndrome, Crohn'sdisease, psoriasis, contact dermatitis or delayed hypersensitivityreactions.

In one embodiment the use of a compound of Formula (I) or a saltthereof, for the treatment of cancer, polycythemia vera, essentialthrombocytosis, myelofibrosis, chronic myelogenous leukemia (CML),rheumatoid arthritis, inflammatory bowel syndrome, Crohn's disease,psoriasis, contact dermatitis or delayed hypersensitivity reactions isprovided.

In one embodiment a composition that is formulated for administration byinhalation is provided.

In one embodiment a metered dose inhaler that comprises a compound ofFormula (I) or a salt thereof is provided.

In one embodiment the compound of Formula (I) or a salt thereof is atleast five-times more potent as an inhibitor of JAK1 than as aninhibitor of JAK2.

In one embodiment the compound of Formula (I) or a salt thereof is atleast ten-times more potent as an inhibitor of JAK1 than as an inhibitorof JAK2.

In one embodiment the compound of Formula (I) or a salt thereof is atleast five-times more potent as an inhibitor of JAK1 than as aninhibitor of JAK3.

In one embodiment the compound of Formula (I) or a salt thereof is atleast ten-times more potent as an inhibitor of JAK1 than as an inhibitorof JAK3.

In one embodiment a method for treating hair loss in a mammal comprisingadministering a compound of Formula (I) or a salt thereof to the mammalis provided.

In one embodiment the use of a compound of Formula (I) or a salt thereoffor the treatment of hair loss is provided.

In one embodiment the use of a compound of Formula (I) or a salt thereofto prepare a medicament for treating hair loss in a mammal is provided.

Synthesis of Janus Kinase Inhibitor Compounds

Compounds of the invention may be synthesized by synthetic routesdescribed herein. In certain embodiments, processes well-known in thechemical arts can be used, in addition to, or in light of, thedescription contained herein. The starting materials are generallyavailable from commercial sources such as Aldrich Chemicals (Milwaukee,Wis.) or are readily prepared using methods well known to those skilledin the art (e.g., prepared by methods generally described in Louis F.Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley,N.Y. (1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4,Aufl. ed. Springer-Verlag, Berlin, including supplements (also availablevia the Beilstein online database)), or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds may be prepared singly or as compound libraries comprising atleast 2, for example 5 to 1,000 compounds, or 10 to 100 compounds.Libraries of compounds may be prepared by a combinatorial ‘split andmix’ approach or by multiple parallel syntheses using either solutionphase or solid phase chemistry, by procedures known to those skilled inthe art. Thus according to a further aspect of the invention there isprovided a compound library comprising at least 2 compounds of theinvention, such as a compound of Formula (I).

For illustrative purposes, reaction Schemes below provide routes forsynthesizing the compounds of the invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used. Although somespecific starting materials and reagents are depicted in the Schemes anddiscussed below, other starting materials and reagents can besubstituted to provide a variety of derivatives or reaction conditions.In addition, many of the compounds prepared by the methods describedbelow can be further modified in light of this disclosure usingconventional chemistry well known to those skilled in the art.

In the preparation of compounds of the invention, protection of remotefunctionality (e.g., primary or secondary amine) of intermediates may benecessary. The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. Suitable amino-protecting groups include acetyl,trifluoroacetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Other conversions commonly used in the synthesis of compounds of theinvention, and which can be carried out using a variety of reagents andconditions, include the following:

-   (1) Reaction of a carboxylic acid with an amine to form an amide.    Such a transformation can be achieved using various reagents known    to those skilled in the art but a comprehensive review can be found    in Tetrahedron, 2005, 61, 10827-10852.-   (2) Reaction of a primary or secondary amine with an aryl halide or    pseudo halide, e.g., a triflate, commonly known as a    “Buchwald-Hartwig cross-coupling,” can be achieved using a variety    of catalysts, ligands and bases. A review of these methods is    provided in Comprehensive Organic Name Reactions and Reagents, 2010,    575-581.-   (3) A palladium cross-coupling reaction between an aryl halide and a    vinyl boronic acid or boronate ester. This transformation is a type    of “Suzuki-Miyaura cross-coupling,” a class of reaction that has    been thoroughly reviewed in Chemical Reviews, 1995, 95(7),    2457-2483.-   (4) The hydrolysis of an ester to give the corresponding carboxylic    acid is well known to those skilled in the art and conditions    include: for methyl and ethyl esters, the use of a strong aqueous    base such as lithium, sodium or potassium hydroxide or a strong    aqueous mineral acid such as HCl; for a tert-butyl ester, hydrolysis    would be carried out using acid, for example, HCl in dioxane or    trifluoroacetic acid (TFA) in dichloromethane (DCM).

Compounds of formula 4 may be prepared by general synthetic methods asshown in Scheme 1.

Compounds of formula 2 can be synthesized by treatment of aniline 1 withvarious acid chlorides in a suitable organic solvent such as, but notlimited to, dichloromethane (DCM) at a temperature ranging from 0° C. toroom temperature and for a time varying from about 30 min to 48 hrs.Alternatively, compounds of formula 2 can be prepared by treatment ofaniline 1 with various carboxylic acids in the presence of an amidecoupling reagent such as, but not limited to,(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluorophosphate) (HATU) in a suitable organic solvent such as,but not limited to, N,N-dimethylformamide (DMF) at a temperature rangingfrom room temperature to 65° C. for a time of about 12 hours.Deprotection of the N-tert-butoxycarbonyl (Boc) group of 2 using aprotic acid such as, but not limited to, trifluoroacetic acid orhydrochloric acid at about room temperature readily affords compounds offormula 3. Compounds of formula 4 can be synthesized through reductiveamination using compounds of formula 3 and the appropriate aldehyde orketone in the presence of a reducing agent such as, but not limited to,sodium triacetoxyborohydride in a suitable organic solvent such as, butnot limited to, dichloromethane at about room temperature and for a timevarying from about 30 minutes to 48 hours. Alternatively, compounds offormula 4 can be synthesized through direct alkylation of the piperidineof 3 using an alkyl iodide/bromide/mesylate/triflate in the presense ofa base such as, but not limited to, diisopropylethylamine (DIEA) ortriethylamine (TEA) in a suitable organic solvent such as, but notlimited to, DCM or DMF at a temperature ranging from about 0° C. toabout room temperature. Treatment of 4 (wherein R^(g) includes asuitable group such as for example Cl, Br, I, OTf, etc.) with aryl,heteroaryl or heterocyclic boronic acid or boronate ester underpalladium catalyst conditions such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in thepresence of an inorganic base such as, but not limited to, potassiumcarbonate in an organic solvent such as, but not limited to, 1,4-dioxaneat an elevated temperature affords the corresponding aryl, heteroaryl orheterocyclic substituted compound.

Compounds of formula 9 may be prepared by general synthetic methods asshown in Scheme 2.

Deprotection of the Boc group of 1 using a protic acid such as, but notlimited to, trifluoroacetic acid or hydrochloric acid at about roomtemperature readily affords compound 7. Compounds of formula 8 can besynthesized through reductive amination by treatment of 7 and theappropriate aldehyde or ketone in the presence of a reducing agent suchas, but not limited to, sodium triacetoxyborohydride in a suitableorganic solvent such as, but not limited to, dichloromethane at aboutroom temperature and for a time varying from about 6 hrs to 12 hrs.Alternatively, compounds of formula 8 can be synthesized through directalkylation of the piperidine of 7 using an alkyliodide/bromide/mesylate/triflate in the presense of a base such as, butnot limited to, diisopropylethylamine or triethylamine in a suitableorganic solvent such as, but not limited to, DCM or DMF at a temperatureranging from about 0° C. to about room temperature. Treatment ofcompounds of formula 8 with various acid chlorides in a suitable organicsolvent such as, but not limited to, dichloromethane (DCM) at atemperature ranging from 0° C. to room temperature and for a timevarying from about 30 min to 12 hours to afford compounds of formula 9.Alternatively, compounds of formula 9 can be prepared by treatment ofaniline 8 with various carboxylic acids in the presence of an amidecoupling reagent such as, but not limited to, HATU in a suitable organicsolvent such as, but not limited to, DMF at a temperature ranging fromroom temperature to 65° C. for a time of about 12 hours.

Compounds of formula 10, 11 and 12 may be prepared by general syntheticmethods as shown in Scheme 3.

Compounds of formula 10 can be synthesized by treatment of 3 withvarious substituted 4-nitro carbonates and an organic base such as, butnot limited to, triethylamine in a suitable organic solvent such as, butnot limited to, ethanol (EtOH) at about room temperature and for a timevarying from about 30 minutes to 12 hours. Likewise, other carbamateformation methods can be employed such as, but not limited to, treatmentof compound 3 with alkyl or aryl chloroformates. Treatment of compoundsof formula 3 with an appropriately substituted oxirane, lithiumperchlorate and an organic base such as, but not limited to, DIEA in asuitable organic solvent such as, but not limited to, acetonitrile atabout room temperature and for a time varying from about 6 hours to 16hours afforded compounds of formula 11. Compounds of formula 12 can beprepared by treatment of piperidine 3 with various carboxylic acids inthe presence of an amide coupling reagent such as, but not limited to,HATU in a suitable organic solvent such as, but not limited to, DMF at atemperature ranging from room temperature to 65° C. for a time of about12 hours. From compound 3, compounds of formula 13 can be formed bytreatment of compound 3 with carbonyldiimidazole, an organic base suchas, but not limited to, DIEA in an organic solvent such as, but notlimited to, 1-methyl-2-pyrrolidinone for a time ranging from 1 hr to 24hrs at a temperature of about 80° C. Alternatively other methods can beused to form compounds of formula 13 such as, but not limited to,treatment of compound 3 with various substituted isocyanates.

Compounds of formula 17 may be prepared by general synthetic methods asshown in Scheme 4.

Compounds of formula 15 can be synthesized by treatment of aniline 14with various acid chlorides in a suitable organic solvent such as, butnot limited to, dichloromethane (DCM) at a temperature ranging from 0°C. to room temperature and for a time varying from about 30 minutes to48 hours. Alternatively, compounds of formula 15 can be prepared bytreatment of aniline 14 with various carboxylic acids in the presence ofan amide coupling reagent such as, but not limited to, HATU in asuitable organic solvent such as, but not limited to, DMF at atemperature ranging from room temperature to 65° C. for a time of about12 hours. Deprotection of the acetal group of 15 using a protic acidsuch as, but not limited to, trifluoroacetic acid or hydrochloric acidat about room temperature readily affords ketone 16. Compounds offormula 17 can be synthesized through reductive amination usingcompounds of formula 16 and the appropriately substituted amine in thepresence of a reducing agent such as, but not limited to, sodiumtriacetoxyborohydride in a suitable organic solvent such as, but notlimited to, dichloromethane at about room temperature and for a timevarying from about 6 hours to 12 hours.

Compounds of formula 1 may be prepared by general synthetic methods asshown in Scheme 5.

Treatment of 18 with diethyl (cyanomethyl)phosphonate in tetrahydrofuranwith sodium hydride at a temperature ranging from 0° C. to about roomtemperature afforded compound 19. Compound 20 can be formed from the1,4-conjugate addition of 3-amino-1H-pyrazole-4-carboxamide and compound19 in acetonitrile in presence of an organic base such as, but notlimited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at about roomtemperature for about 48 hrs.

Compounds of formula 29 may be prepared by general synthetic methods asshown in Scheme 6.

Compounds of formula 29 can be prepared using similar general methodsoutlined in Scheme 1 and Scheme 5.

Compounds of formula 30, 31, 32, 33, 34 and 35 may be prepared bygeneral synthetic methods as shown in Scheme 7.

Compounds of formula 30-35 can be synthesized directly from theircorresponding acetonitrile analogues 4-6 and 23-25. Treatment of the 4-6and 23-25 individually with diisobutyl aluminum hydride in a suitableorganic solvent such as, but not limited to, DCM at a temperature of−78° C. and for a time varying from about 2 to 4 hrs afforded thecorresponding aldehydes. Treatment of these aldehydes withethane-1,2-dithiol and an acid such as, but not limited to,4-methylbenzenesulfonic acid in a suitable organic solvent such as, butnot limited to, DCM at a temperature ranging from room temperature to60° C. and for a time varying from about 2 to 6 hrs produced thecorresponding dithianes. The dithianes can be treated with Raney Niunder a hydrogen atmosphere in a suitable organic solvent such as, butnot limited to, THF at a temperature of room temperature for a timevarying from about 8 to 24 hrs to yield the individual correspondingethyl analogues 30-35. See, e.g., WO 2016/061751 and WO 2016/064935 forfurther examples.

It will be appreciated that where appropriate functional groups exist,compounds of various formulae or any intermediates used in theirpreparation may be further derivatized by one or more standard syntheticmethods employing condensation, substitution, oxidation, reduction, orcleavage reactions. Particular substitution approaches includeconventional alkylation, arylation, heteroarylation, acylation,sulfonylation, halogenation, nitration, formylation and couplingprocedures.

In a further example, primary amine or secondary amine groups may beconverted into amide groups (—NHCOR′ or —NRCOR′) by acylation. Acylationmay be achieved by reaction with an appropriate acid chloride in thepresence of a base, such as triethylamine, in a suitable solvent, suchas dichloromethane, or by reaction with an appropriate carboxylic acidin the presence of a suitable coupling agent such HATU(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) in a suitable solvent such as dichloromethane.Similarly, amine groups may be converted into sulphonamide groups(—NHSO₂R′ or —NR″SO₂R′) groups by reaction with an appropriate sulphonylchloride in the presence of a suitable base, such as triethylamine, in asuitable solvent such as dichloromethane. Primary or secondary aminegroups can be converted into urea groups (—NHCONR′R″ or —NRCONR′R″) byreaction with an appropriate isocyanate in the presence of a suitablebase such as triethylamine, in a suitable solvent, such asdichloromethane.

An amine (—NH₂) may be obtained by reduction of a nitro (—NO₂) group,for example by catalytic hydrogenation, using for example hydrogen inthe presence of a metal catalyst, for example palladium on a supportsuch as carbon in a solvent such as ethyl acetate or an alcohol e.g.,methanol. Alternatively, the transformation may be carried out bychemical reduction using for example a metal, e.g., tin or iron, in thepresence of an acid such as hydrochloric acid.

In a further example, amine (—CH₂NH₂) groups may be obtained byreduction of nitriles (—CN), for example by catalytic hydrogenationusing for example hydrogen in the presence of a metal catalyst, forexample palladium on a support such as carbon, or Raney nickel, in asolvent such as an ether e.g., a cyclic ether such as tetrahydrofuran,at an appropriate temperature, for example from about −78° C. to thereflux temperature of the solvent.

In a further example, amine (—NH₂) groups may be obtained fromcarboxylic acid groups (—CO₂H) by conversion to the corresponding acylazide (—CON₃), Curtius rearrangement and hydrolysis of the resultantisocyanate (—N═C═O).

Aldehyde groups (—CHO) may be converted to amine groups (—CH₂NR′R″)) byreductive amination employing an amine and a borohydride, for examplesodium triacetoxyborohydride or sodium cyanoborohydride, in a solventsuch as a halogenated hydrocarbon, for example dichloromethane, or analcohol such as ethanol, where necessary in the presence of an acid suchas acetic acid at around ambient temperature.

In a further example, aldehyde groups may be converted into alkenylgroups (—CH═CHR′) by the use of a Wittig or Wadsworth-Emmons reactionusing an appropriate phosphorane or phosphonate under standardconditions known to those skilled in the art.

Aldehyde groups may be obtained by reduction of ester groups (such as—CO₂Et) or nitriles (—CN) using diisobutylaluminum hydride in a suitablesolvent such as toluene. Alternatively, aldehyde groups may be obtainedby the oxidation of alcohol groups using any suitable oxidizing agentknown to those skilled in the art.

Ester groups (—CO₂R′) may be converted into the corresponding acid group(—CO₂H) by acid- or base-catalyzed hydrolysis, depending on the natureof R. If R is t-butyl, acid-catalyzed hydrolysis can be achieved forexample by treatment with an organic acid such as trifluoroacetic acidin an aqueous solvent, or by treatment with an inorganic acid such ashydrochloric acid in an aqueous solvent.

Carboxylic acid groups (—CO₂H) may be converted into amides (CONHR′ or—CONR′R″) by reaction with an appropriate amine in the presence of asuitable coupling agent, such as HATU, in a suitable solvent such asdichloromethane.

In a further example, carboxylic acids may be homologated by one carbon(i.e —CO₂H to —CH₂CO₂H) by conversion to the corresponding acid chloride(—COCl) followed by Arndt-Eistert synthesis.

In a further example, —OH groups may be generated from the correspondingester (e.g., —CO₂R′), or aldehyde (—CHO) by reduction, using for examplea complex metal hydride such as lithium aluminum hydride in diethylether or tetrahydrofuran, or sodium borohydride in a solvent such asmethanol. Alternatively, an alcohol may be prepared by reduction of thecorresponding acid (—CO₂H), using for example lithium aluminum hydridein a solvent such as tetrahydrofuran, or by using borane in a solventsuch as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogenatoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g.,trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g.,p-toluenesulfonyloxy group using conditions known to those skilled inthe art. For example, an alcohol may be reacted with thioyl chloride ina halogenated hydrocarbon (e.g., dichloromethane) to yield thecorresponding chloride. A base (e.g., triethylamine) may also be used inthe reaction.

In another example, alcohol, phenol or amide groups may be alkylated bycoupling a phenol or amide with an alcohol in a solvent such astetrahydrofuran in the presence of a phosphine, e.g., triphenylphosphineand an activator such as diethyl-, diisopropyl, ordimethylazodicarboxylate. Alternatively alkylation may be achieved bydeprotonation using a suitable base e.g., sodium hydride followed bysubsequent addition of an alkylating agent, such as an alkyl halide.

Aromatic halogen substituents in the compounds may be subjected tohalogen-metal exchange by treatment with a base, for example a lithiumbase such as n-butyl or t-butyl lithium, optionally at a lowtemperature, e.g., around −78° C., in a solvent such as tetrahydrofuran,and then quenched with an electrophile to introduce a desiredsubstituent. Thus, for example, a formyl group may be introduced byusing N,N-dimethylformamide as the electrophile. Aromatic halogensubstituents may alternatively be subjected to metal (e.g., palladium orcopper) catalyzed reactions, to introduce, for example, acid, ester,cyano, amide, aryl, heteroaryl, alkenyl, alkynyl, thio- or aminosubstituents. Suitable procedures which may be employed include thosedescribed by Heck, Suzuki, Stille, Buchwald or Hartwig.

Aromatic halogen substituents may also undergo nucleophilic displacementfollowing reaction with an appropriate nucleophile such as an amine oran alcohol. Advantageously, such a reaction may be carried out atelevated temperature in the presence of microwave irradiation.

Methods of Separation

In each of the exemplary Schemes it may be advantageous to separatereaction products from one another or from starting materials. Thedesired products of each step or series of steps is separated orpurified (hereinafter separated) to the desired degree of homogeneity bythe techniques common in the art. Typically such separations involvemultiphase extraction, crystallization or trituration from a solvent orsolvent mixture, distillation, sublimation, or chromatography.Chromatography can involve any number of methods including, for example:reverse-phase and normal phase; size exclusion; ion exchange;supercritical fluid; high, medium, and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture witha reagent selected to bind to or render otherwise separable a desiredproduct, unreacted starting material, reaction by product, or the like.Such reagents include adsorbents or absorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature ofthe materials involved. Example separation methods include boilingpoint, and molecular weight in distillation and sublimation, presence orabsence of polar functional groups in chromatography, stability ofmaterials in acidic and basic media in multiphase extraction, and thelike. One skilled in the art will apply techniques most likely toachieve the desired separation.

Diastereomeric mixtures can be separated into their individualdiastereoisomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereoisomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn or supercritical fluid chromatography.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S., Stereochemistry of OrganicCompounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H.,J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: DrugStereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically purechiral bases such as brucine, quinine, ephedrine, strychnine,α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetriccompounds bearing acidic functionality, such as carboxylic acid andsulfonic acid. The diastereomeric salts may be induced to separate byfractional crystallization or ionic chromatography. For separation ofthe optical isomers of amino compounds, addition of chiral carboxylic orsulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelicacid, or lactic acid can result in formation of the diastereomericsalts.

Alternatively, the substrate to be resolved is reacted with oneenantiomer of a chiral compound to form a diastereomeric pair (Eliel, E.and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons,Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrumfor the presence of the two atropisomeric enantiomers or diastereomers.Stable diastereomers of atropisomeric compounds can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (WO 96/15111,incorporated herein by reference). By method (3), a racemic mixture oftwo enantiomers can be separated by chromatography using a chiralstationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapmanand Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378(1990)). Enriched or purified enantiomers can be distinguished bymethods used to distinguish other chiral molecules with asymmetriccarbon atoms, such as optical rotation and circular dichroism. Theabsolute stereochemistry of chiral centers and enantiomers can bedetermined by x-ray crystallography.

Positional isomers, for example E and Z forms, of compounds of Formula(I) and intermediates for their synthesis, may be observed bycharacterization methods such as NMR and analytical HPLC. For certaincompounds where the energy barrier for interconversion is sufficientlyhigh, the E and Z isomers may be separated, for example by preparatoryHPLC.

Pharmaceutical Compositions and Administration

The compounds with which the invention is concerned are JAK kinaseinhibitors, such as JAK1 inhibitors, and are useful in the treatment ofseveral diseases, for example, inflammatory diseases, such as asthma.

Accordingly, another embodiment provides pharmaceutical compositions ormedicaments containing a compound of the invention, such as a compoundof Formula (I), or a salt thereof (e.g., a pharmaceutically acceptablesalt), and a pharmaceutically acceptable carrier, diluent or excipient,as well as methods of using the compounds of the invention to preparesuch compositions and medicaments.

In one example, a compound of Formula (I) may be formulated by mixing atambient temperature at the appropriate pH, and at the desired degree ofpurity, with physiologically acceptable carriers, i.e., carriers thatare non-toxic to recipients at the dosages and concentrations employedinto a galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, buttypically ranges anywhere from about 3 to about 8. In one example, acompound of Formula (I) is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of the present invention, such as acompound of Formula (I) are sterile. The compound may be stored, forexample, as a solid or amorphous composition, as a lyophilizedformulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners.

It will be understood that the specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, route of administration, rate ofexcretion, drug combination and the severity of the particular diseaseundergoing treatment. Optimum dose levels and frequency of dosing willbe determined by clinical trial, as is required in the pharmaceuticalart. In general, the daily dose range for oral administration will liewithin the range of from about 0.001 mg to about 100 mg per kg bodyweight of a human, often 0.01 mg to about 50 mg per kg, for example 0.1to 10 mg per kg, in single or divided doses. In general, the daily doserange for inhaled administration will lie within the range of from about0.1 μg to about 1 mg per kg body weight of a human, preferably 0.1 μg to50 μg per kg, in single or divided doses. On the other hand, it may benecessary to use dosages outside these limits in some cases.

The compounds of the invention, such as a compound of Formula (I), maybe administered by any suitable means, including oral, topical(including buccal and sublingual), rectal, vaginal, transdermal,parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal,intrathecal, inhaled and epidural and intranasal, and, if desired forlocal treatment, intralesional administration. Parenteral infusionsinclude intramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. In some embodiments, inhaled administrationis employed.

The compounds of the present invention, such as a compound of Formula(I), may be administered in any convenient administrative form, e.g.,tablets, powders, capsules, lozenges, granules, solutions, dispersions,suspensions, syrups, sprays, vapors, suppositories, gels, emulsions,patches, etc. Such compositions may contain components conventional inpharmaceutical preparations, e.g., diluents (e.g., glucose, lactose orto mannitol), carriers, pH modifiers, buffers, sweeteners, bulkingagents, stabilizing agents, surfactants, wetting agents, lubricatingagents, emulsifiers, suspending agents, preservatives, antioxidants,opaquing agents, glidants, processing aids, colorants, perfuming agents,flavoring agents, other known additives as well as further activeagents.

Suitable carriers and excipients are well known to those skilled in theart and are described in detail in, e.g., Ansel, Howard C., et al.,Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R.,et al. Remington: The Science and Practice of Pharmacy. Philadelphia:Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook ofPharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Forexample, carriers include solvents, dispersion media, coatings,surfactants, antioxidants, preservatives (e.g., antibacterial agents,antifungal agents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, gels, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, pp 1289-1329, 1990). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.Exemplary excipients include dicalcium phosphate, mannitol, lactose,starch, magnesium stearate, sodium saccharine, cellulose, magnesiumcarbonate or combinations thereof. A pharmaceutical composition maycomprise different types of carriers or excipients depending on whetherit is to be administered in solid, liquid or aerosol form, and whetherit need to be sterile for such routes of administration.

For example, tablets and capsules for oral administration may be in unitdose presentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers, for example, lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example, magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, or acceptable wettingagents such as sodium lauryl sulfate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample, methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavoring or coloring agents.

For topical application to the skin, a compound may be made up into acream, lotion or ointment. Cream or ointment formulations which may beused for the drug are conventional formulations well known in the art,for example as described in standard textbooks of pharmaceutics such asthe British Pharmacopoeia.

Compounds of the invention, such as a compound of Formula (I), may alsobe formulated for inhalation, for example, as a nasal spray, or drypowder or aerosol inhalers. For delivery by inhalation, the compound istypically in the form of microparticles, which can be prepared by avariety of techniques, including spray-drying, freeze-drying andmicronisation. Aerosol generation can be carried out using, for example,pressure-driven jet atomizers or ultrasonic atomizers, such as by usingpropellant-driven metered aerosols or propellant-free administration ofmicronized compounds from, for example, inhalation capsules or other“dry powder” delivery systems.

By way of example, a composition of the invention may be prepared as asuspension for delivery from a nebulizer or as an aerosol in a liquidpropellant, for example, for use in a pressurized metered dose inhaler(PMDI). Propellants suitable for use in a PMDI are known to the skilledperson, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCl₂F₂) andHFA-152 (CH₄F₂ and isobutane).

In some embodiments, a composition of the invention is in dry powderform, for delivery using a dry powder inhaler (DPI). Many types of DPIare known.

Microparticles for delivery by administration may be formulated withexcipients that aid delivery and release. For example, in a dry powderformulation, microparticles may be formulated with large carrierparticles that aid flow from the DPI into the lung. Suitable carrierparticles are known, and include lactose particles; they may have a massmedian aerodynamic diameter of, for example, greater than 90 μm.

In the case of an aerosol-based formulation, an example is:

Compound of the invention* 24 mg/canister Lecithin, NF Liq. Conc. 1.2mg/canister Trichlorofluoromethane, NF 4.025 g/canisterDichlorodifluoromethane, NF 12.15 g/canister. *Such as a compound ofFormula (I).

A compound, such as a compound of Formula (I), may be dosed as describeddepending on the inhaler system used. In addition to the compound, theadministration forms may additionally contain excipients as describedabove, or, for example, propellants (e.g., Frigen in the case of meteredaerosols), surface-active substances, emulsifiers, stabilizers,preservatives, flavorings, fillers (e.g., lactose in the case of powderinhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are availablewith which aerosols of optimum particle size can be generated andadministered, using an inhalation technique which is appropriate for thepatient. In addition to the use of adaptors (spacers, expanders) andpear-shaped containers (e.g., Nebulator®, Volumatic®), and automaticdevices emitting a puffer spray (Autohaler®), for metered aerosols, inthe case of powder inhalers in particular, a number of technicalsolutions are available (e.g., Diskhaler®, Rotadisk®, Turbohaler® or theinhalers, for example, as described in U.S. Pat. No. 5,263,475,incorporated herein by reference). Additionally, compounds of theinvention, such as a compound of Formula (I), may be delivered inmulti-chamber devices thus allowing for delivery of combination agents.

The compound, such as a compound of Formula (I), may also beadministered parenterally in a sterile medium. Depending on the vehicleand concentration used, the compound can either be suspended ordissolved in the vehicle. Advantageously, adjuvants such as a localanaesthetic, preservative or buffering agents can be dissolved in thevehicle.

Targeted Inhaled Drug Delivery

Optimisation of drugs for delivery to the lung by topical (inhaled)administration has been recently reviewed (Cooper, A. E. et al. Curr.Drug Metab. 2012, 13, 457-473). Due to limitations in the deliverydevice, the dose of an inhaled drug is likely to be low (approximately<1 mg/day) in humans which necessitates highly potent molecules. Forcompounds destined to be delivered via dry powder inhalation there isalso a requirement to be able to generate crystalline forms of thecompound that can be micronized to 1-5 μm in size. Additionally, thecompound needs to maintain a sufficient concentration in the lung over agiven time period so as to be able to exert a pharmacological effect ofthe desired duration, and for pharmacological targets where systemicinhibition of said target is undesired, to have a low systemic exposure.The lung has an inherently high permeability to both large molecules(proteins, peptides) as well as small molecules with concomitant shortlung half-lives, thus it is necessary to attenuate the lung absorptionrate through modification of one or more features of the compounds:minimizing membrane permeability, reducing dissolution rate, orintroducing a degree of basicity into the compound to enhance binding tothe phospholipid-rich lung tissue or through trapping in acidicsub-cellular compartments such as lysosomes (pH 5). Accordingly, in someembodiments, compounds of the present invention exhibit one or more ofthese features.

Methods of Treatment with and Uses of Janus Kinase Inhibitors

The compounds of the present invention, such as a compound of Formula(I), inhibit the activity of a Janus kinase, such as JAK1 kinase. Forexample, a compound of the present invention, such as a compound ofFormula (I), inhibits the phosphorylation of signal transducers andactivators of transcription (STATs) by JAK1 kinase as well as STATmediated cytokine production. Compounds of the present invention, suchas a compound of Formula (I), are useful for inhibiting JAK1 kinaseactivity in cells through cytokine pathways, such as IL-6, IL-15, IL-7,IL-2, IL-4, IL-9, IL-10, IL-13, IL-21, G-CSF, IFNalpha, IFNbeta orIFNgamma pathways. Accordingly, in one embodiment is to provided amethod of contacting a cell with a compound of the present invention,such as a compound of Formula (I), to inhibit a Janus kinase activity inthe cell (e.g., JAK1 activity).

The compounds of the present invention, such as compounds of Formula(I), can be used for the treatment of immunological disorders driven byaberrant IL-6, IL-15, IL-7, IL-2, IL-4, IL9, IL-10, IL-13, IL-21, G-CSF,IFNalpha, IFNbeta or IFNgamma cytokine signaling.

Accordingly, one embodiment includes compounds of the present invention,such as a compound of Formula (I), for use in therapy.

In some embodiments, there is provided use a compound of the presentinvention, such as a compound of Formula (I), in the treatment of aninflammatory disease. Further provided is use of a compound of thepresent invention, such as a compound of Formula (I), for thepreparation of a medicament for the treatment of an inflammatorydisease, such as asthma. Also provided is a compound of the presentinvention, such as a compound of Formula (I), for use in the treatmentof an inflammatory disease, such as asthma.

Another embodiment includes a method of preventing, treating orlessening the severity of a disease or condition, such as asthma,responsive to the inhibition of a Janus kinase activity, such as JAK1kinase activity, in a patient. The method can include the step ofadministering to a patient a therapeutically effective amount of acompound of the present invention, such as a compound of Formula (I). Inone embodiment, the disease or condition responsive to the inhibition ofa Janus kinase, such as JAK1 kinase, is asthma.

In one embodiment, the disease or condition is cancer, stroke, diabetes,hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer'sdisease, cystic fibrosis, viral disease, autoimmune diseases,atherosclerosis, restenosis, psoriasis, rheumatoid arthritis,inflammatory bowel disease, asthma, allergic disorders, inflammation,neurological disorders, a hormone-related disease, conditions associatedwith organ transplantation (e.g., transplant rejection),immunodeficiency disorders, destructive bone disorders, proliferativedisorders, infectious diseases, conditions associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, CNS disorders or amyeloproliferative disorder.

In one embodiment, the inflammatory disease is rheumatoid arthritis,psoriasis, asthma, inflammatory bowel disease, contact dermatitis ordelayed hypersensitivity reactions. In one embodiment, the autoimmunedisease is rheumatoid arthritis, lupus or multiple sclerosis.

In one embodiment, the cancer is breast, ovary, cervix, prostate,testis, penile, genitourinary tract, seminoma, esophagus, larynx,gastric, stomach, gastrointestinal, skin, keratoacanthoma, follicularcarcinoma, melanoma, lung, small cell lung carcinoma, non-small celllung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of thelung, colon, pancreas, thyroid, papillary, bladder, liver, biliarypassage, kidney, bone, myeloid disorders, lymphoid disorders, hairycells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivarygland, pharynx, small intestine, colon, rectum, anal, renal, prostate,vulval, thyroid, large intestine, endometrial, uterine, brain, centralnervous system, cancer of the peritoneum, hepatocellular cancer, headcancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the disease is a myeloproliferative disorder. In oneembodiment, the myeloproliferative disorder is polycythemia vera,essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia(CML).

Another embodiment includes the use of a compound of the presentinvention, such as a compound of Formula (I), for the manufacture of amedicament for the treatment of a disease described herein (e.g., aninflammatory disorder, an immunological disorder or cancer). In oneembodiment, the invention provides a method of treating a disease orcondition as described herein e.g., an inflammatory disorder, animmunological disorder or cancer) by targeting inhibition of a JAKkinase, such as JAK1.

Combination Therapy

The compounds of the present invention, such as a compound of Formula(I), may be employed alone or in combination with other agents fortreatment. The second compound of a pharmaceutical composition or dosingregimen typically has complementary activities to the compound of thisinvention such that they do not adversely affect each other. Such agentsare suitably present in combination in amounts that are effective forthe purpose intended. The compounds may be administered together in aunitary pharmaceutical composition or separately and, when administeredseparately this may occur simultaneously or sequentially. Suchsequential administration may be close or remote in time.

For example, other compounds may be combined with compounds with whichthe invention is concerned for the prevention or treatment ofinflammatory diseases, such as asthma. Thus the present invention isalso concerned with pharmaceutical compositions comprising atherapeutically effective amount of a compound of the invention and oneor more other therapeutic agents. Suitable therapeutic agents for acombination therapy with compounds of the invention include, but are notlimited to: an adenosine A2A receptor antagonist; an anti-infective; anon-steroidal Glucocorticoid Receptor (GR Receptor) agonist; anantioxidant; a J32 adrenoceptor agonist; a CCR1 antagonist; a chemokineantagonist (not CCR1); a corticosteroid; a CRTh2 antagonist; a DP1antagonist; a formyl peptide receptor antagonist; a histone deacetylaseactivator; a chloride channel hCLCA1 blocker; an epithelial sodiumchannel blocker (ENAC blocker; an inter-cellular adhesion molecule 1blocker (ICAM blocker); an IKK2 inhibitor; a JNK inhibitor; acyclooxygenase inhibitor (COX inhibitor); a lipoxygenase inhibitor; aleukotriene receptor antagonist; a dual J32 adrenoceptor agonist/M3receptor antagonist (MABA compound); a MEK-1 inhibitor; amyeloperoxidase inhibitor (MPO inhibitor); a muscarinic antagonist; ap38 MAPK inhibitor; a phosphodiesterase PDE4 inhibitor; aphosphatidylinositol 3-kinase δ inhibitor (PI3-kinase δ inhibitor); aphosphatidylinositol 3-kinase γ inhibitor (PI3-kinase γ inhibitor); aperoxisome proliferator activated receptor agonist (PPARγ agonist); aprotease inhibitor; a retinoic acid receptor modulator (RAR γmodulator); a statin; a thromboxane antagonist; a TLR7 receptor agonist;or a vasodilator.

In addition, compounds of the invention, such as a compound of Formula(I), may be combined with: (1) corticosteroids, such as alclometasonedipropionate, amelometasone, beclomethasone dipropionate, budesonide,butixocort propionate, biclesonide, blobetasol propionate,desisobutyrylciclesonide, dexamethasone, dtiprednol dicloacetate,fluocinolone acetonide, fluticasone furoate, fluticasone propionate,loteprednol etabonate (topical) or mometasone furoate; (2)β2-adrenoreceptor agonists such as salbutamol, albuterol, terbutaline,fenoterol, bitolterol, carbuterol, clenbuterol, pirbuterol, rimoterol,terbutaline, tretoquinol, tulobuterol and long acting β2-adrenoreceptoragonists such as metaproterenol, isoproterenol, isoprenaline,salmeterol, indacaterol, formoterol (including formoterol fumarate),arformoterol, carmoterol, abediterol, vilanterol trifenate, olodaterol;(3) corticosteroid/long acting β2 agonist combination products such assalmeterol/fluticasone propionate (Advair®, also sold as Seretide®),formoterol/budesonide (Symbicort®), formoterol/fluticasone propionate(Flutiform®), formoterol/ciclesonide, formoterol/mometasone furoate,indacaterol/mometasone furoate, vilanterol trifenate/fluticasonefuroate, or arformoterol/ciclesonide; (4) anticholinergic agents, forexample, muscarinic-3 (M3) receptor antagonists such as ipratropiumbromide, tiotropium bromide, aclidinium (LAS-34273), glycopyrroniumbromide, umeclidinium bromide; (5) M3-anticholinergic/β2-adrenoreceptoragonist combination products such as vilanterol/umeclidinium (Anoro®Ellipta®), olodaterol/tiotropium bromide, glycopyrroniumbromide/indacaterol (Ultibro®, also sold as Xoterna®), fenoterolhydrobromide/ipratropium bromide (Berodual®), albuterolsulfate/ipratropium bromide (Combivent®), formoterolfumarate/glycopyrrolate, or aclidinium bromide/formoterol (6) dualpharmacology M3-anticholinergic/β2-adrenoreceptor agonists such asbatefenterol succinate, AZD-2115 or LAS-190792; (7) leukotrienemodulators, for example, leukotriene antagonists such as montelukast,zafirulast or pranlukast or leukotriene biosynthesis inhibitors such aszileuton, or LTB4 antagonists such as amelubant, or FLAP inhibitors suchas fiboflapon, GSK-2190915; (8) phosphodiesterase-IV (PDE-IV) inhibitors(oral or inhaled), such as roflumilast, cilomilast, oglemilast,rolipram, tetomilast, AVE-8112, revamilast, CHF 6001; (9)antihistamines, for example, selective histamine-1 (H1) receptorantagonists such as fexofenadine, citirizine, loratidine or astemizoleor dual H1/H3 receptor antagonists such as GSK 835726, or GSK 1004723;(10) antitussive agents, such as codeine or dextramorphan; (11) amucolytic, for example, N-acetyl cysteine or fudostein; (12) aexpectorant/mucokinetic modulator, for example, ambroxol, hypertonicsolutions (e.g., saline or mannitol) or surfactant; (13) a peptidemucolytic, for example, recombinant human deoxyribonoclease I(dornase-alpha and rhDNase) or helicidin; (14) antibiotics, for exampleazithromycin, tobramycin or aztreonam; (15) non-selective COX-1/COX-2inhibitors, such as ibuprofen or ketoprofen; (16) COX-2 inhibitors, suchas celecoxib and rofecoxib; (17) VLA-4 antagonists, such as thosedescribed in WO97/03094 and WO97/02289, each incorporated herein byreference; (18) TACE inhibitors and TNF-α, inhibitors, for exampleanti-TNF monoclonal antibodies, such as Remicade® and CDP-870 and TNFreceptor immunoglobulin molecules, such as Enbrel®; (19) inhibitors ofmatrix metalloprotease, for example MMP-12; (20) human neutrophilelastase inhibitors, such as BAY-85-8501 or those described inWO2005/026124, WO2003/053930 and WO06/082412, each incorporated hereinby reference; (21) A2b antagonists such as those described inWO2002/42298, incorporated herein by reference; (22) modulators ofchemokine receptor function, for example antagonists of CCR3 and CCR8;(23) compounds which modulate the action of other prostanoid receptors,for example, a thromboxane A₂ antagonist; DP1 antagonists such aslaropiprant or asapiprant CRTH2 antagonists such as OC000459,fevipiprant, ADC 3680 or ARRY 502; (24) PPAR agonists including PPARalpha agonists (such as fenofibrate), PPAR delta agonists, PPAR gammaagonists such as pioglitazone, rosiglitazone and balaglitazone; (25)methylxanthines such as theophylline or aminophylline andmethylxanthine/corticosteroid combinations such astheophylline/budesonide, theophylline/fluticasone propionate,theophylline/ciclesonide, theophylline/mometasone furoate andtheophylline/beclometasone dipropionate; (26) A2a agonists such as thosedescribed in EP1052264 and EP1241176; (27) CXCR2 or IL-8 antagonistssuch as AZD-5069, AZD-4721, danirixin; (28) IL-R signalling modulatorssuch as kineret and ACZ 885; (29) MCP-1 antagonists such as ABN-912;(30) a p38 MAPK inhibitor such as BCT197, JNJ49095397, losmapimod orPH-797804; (31) TLR7 receptor agonists such as AZD 8848; (32) PI3-kinaseinhibitors such as RV1729 or GSK2269557.

In some embodiments, the compounds of the present invention, such as acompound of Formula (I), can be used in combination with one or moreadditional drugs, for example anti-hyperproliferative, anti-cancer,cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agents,such as those agents disclosed in U.S. Publ. Appl. No. 2010/0048557,incorporated herein by reference. A compound of the present invention,such as a compound of Formula (I), can be also used in combination withradiation therapy or surgery, as is known in the art.

Articles of Manufacture

Another embodiment includes an article of manufacture (e.g., a kit) fortreating a disease or disorder responsive to the inhibition of a Januskinase, such as a JAK1 kinase. The kit can comprise:

(a) a first pharmaceutical composition comprising a compound of thepresent invention, such as a compound of Formula (I); and

(b) instructions for use.

In another embodiment, the kit further comprises:

(c) a second pharmaceutical composition, such as a pharmaceuticalcomposition comprising an agent for treatment as described above, suchas an agent for treatment of an inflammatory disorder, or achemotherapeutic agent.

In one embodiment, the instructions describe the simultaneous,sequential or separate administration of said first and secondpharmaceutical compositions to a patient in need thereof.

In one embodiment, the first and second compositions are contained inseparate containers. In another embodiment, the first and secondcompositions are contained in the same container.

Containers for use include, for example, bottles, vials, syringes,blister pack, etc. The containers may be formed from a variety ofmaterials such as glass or plastic. The container includes a compound ofthe present invention, such as a compound of Formula (I), or compositionthereof, which is effective for treating the condition and may have asterile access port (for example the container may be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). The label or package insert indicates that thecompound or composition is used for treating the condition of choice,such as asthma or cancer. In one embodiment, the label or packageinserts indicates that the compound or composition can be used to treata disorder. In addition, the label or package insert may indicate thatthe patient to be treated is one having a disorder characterized byoveractive or irregular Janus kinase activity, such as overactive orirregular JAK1 activity. The label or package insert may also indicatethat the compound or composition can be used to treat other disorders.

Alternatively, or additionally, the kit may further comprise a second(or third) container comprising a pharmaceutically acceptable buffer,such as bacteriostatic water for injection (BWFI), phosphate-bufferedsaline, Ringer's solution or dextrose solution. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare othercompounds of the present invention, and alternative methods forpreparing the compounds are within the scope of this invention. Forexample, the synthesis of non-exemplified compounds according to theinvention may be successfully performed by modifications apparent tothose skilled in the art, e.g., by appropriately protecting interferinggroups, by utilizing other suitable reagents known in the art other thanthose described, or by making routine modifications of reactionconditions. Alternatively, other reactions disclosed herein or known inthe art will be recognized as having applicability for preparing othercompounds of the invention.

EXAMPLES

Although the invention has been described and illustrated with a certaindegree of particularity, it is understood that the present disclosurehas been made only by way of example, and that numerous changes in thecombination and arrangement of parts can be resorted to by those skilledin the art without departing from the spirit and scope of the invention,as defined by the claims.

Examples 1 & 2 (General Procedure A)

1-((1S,4S)-1-(Cyanomethyl)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide&1-((1R,4R)-1-(cyanomethyl)-4-((2,2,2-trifluoroethyl)amino)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

Cyclopropanecarbonyl chloride (750 mg, 7.18 mmol) was added dropwise toa solution of3-amino-1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-1H-pyrazole-4-carboxamide(2.00 g, 6.55 mmol) and DIPEA (1.69 g, 13.1 mmol) in dichloromethane (50mL) at 0° C. The resulting solution was stirred for 5 h at 20° C. andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(10/1). The appropriate fractions were combined and concentrated underreduced pressure to give 1.60 g (65%) of1-(8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a yellow solid. TLC: R_(f)=0.6; DCM/MeOH=10/1.

A solution of1-(8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(1.50 g, 4.02 mmol) in tetrahydrofuran (10 mL) and 4N HCl aqueoussolution (20 mL) was stirred at 20° C. overnight. K₂CO₃ was addedcarefully until the pH reached ˜8. The mixture was extracted with ethylacetate (5×). The organic layers were combined, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (5/1). The appropriate fractions were combinedand concentrated under reduced pressure to afford 0.801 g (56%) of1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-(cyclopropane-carboxamido)-1H-pyrazole-4-carboxamideas a yellow solid. TLC: R_(f)=0.5; DCM/MeOH=10/1.

To a solution1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-cyclopropane-carboxamido)-1H-pyrazole-4-carboxamide(150 mg, 0.455 mmol) in ethanol (8.0 mL) was added2,2,2-trifluoroethan-1-amine (68.0 mg, 0.686 mmol) andtetrakis(propan-2-yloxy)titanium (263 mg, 0.925 mmol) under nitrogen.The reaction mixture was stirred for 2 h at 60° C. AcOH (0.1 mL) andNaBH₃CN (29.0 mg, 0.461 mmol) were added. The resulting solution wasstirred at 60° C. overnight, and concentrated under reduced pressure.The residue was passed through a short pad of silica gel eluting withdichloromethane/methanol (3/1). The appropriate fractions were combinedand concentrated. The residue (150 mg) was further purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,19*150 mm, 5 um; mobile phase, 10 mM NH₄HCO₃ in water and CH₃CN (10.0%CH₃CN up to 28.0% in 8 min); Detector, UV 254 nm to give two fractions.Absolute configuration was arbitrarily assigned to each diastereomer:

Example 1: The first fraction, 28.4 mg as a white solid, LC/MS (MethodA, ESI): [M+H]⁺=413, R_(T)=1.04 min; ¹HNMR (300 MHz, CD₃OD): δ (ppm)8.35 (s, 1H), 3.21-3.06 (m, 3H), 2.91 (s, 2H), 2.79-2.53 (m, 3H),1.84-1.65 (m, 4H), 1.11-0.93 (m, 2H), 0.90-0.85 (m, 4H).

Example 2: The second fraction, 5.6 mg as a white solid, LC/MS (MethodB, ESI): [M+H]⁺=413.1, R_(T)=1.42 min; ¹H NMR (300 MHz, CD₃OD): δ (ppm)8.41 (s, 1H), 3.29-3.10 (m, 4H), 2.78-2.76 (m, 1H), 2.39-2.36 (m, 2H),2.19-2.11 (m, 2H), 1.96-1.85 (m, 3H), 1.68-1.51 (m, 2H), 1.05-0.86 (m,4H).

Example 3 (General Procedure B)

1-(4-(Cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-4-(3-methylureido)-1H-pyrazole-3-carboxamide

Tert-butyl 4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (5.00 g, 14.4 mmol) was added to 4N HCl indioxane (50 mL). The reaction mixture was stirred at room temperaturefor 6 h. The precipitates were collected by filtration and dried underreduced pressure to afford 5.30 g of3-amino-1-[4-(cyanomethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamidehydrochloride as an off-white solid, which was used directly withoutfurther purification. LC/MS (Method G, ESI): [M+H]⁺=249, R_(T)=0.16 min.

To a solution of3-amino-1-[4-(cyanomethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamidehydrochloride (1.00 g, crude from last step) in N,N-dimethylformamide(30 mL) was added triethylamine (710 mg, 7.02 mmol) and2,2,2-trifluoroethyl trifluoromethanesulfonate (980 mg, 4.22 mmol) atroom temperature. The reaction mixture was stirred at room temperatureovernight. The reaction was then quenched by the addition of 40% aqueousmethylamine solution, and concentrated under reduced pressure. Theresidue was partitioned between water and dichloromethane. The aqueousphase was extracted with dichloromethane (2×). The combined organicphases were washed with water and brine, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5). The appropriate fractions were combined and concentrated underreduced pressure to afford 1.10 g (95%) of3-amino-1-[4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamideas a yellow solid. LC/MS (Method G, ESI): [M+H]⁺=331, R_(T)=0.54 min.

To a solution of3-amino-1-[4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamide(100 mg, 0.303 mmol) and DIPEA (78.3 mg, 0.606 mmol) in dichloromethane(30 mL) was added methylcarbamic chloride (34.3 mg, 0.363 mmol) at 0° C.under nitrogen. The reaction mixture was stirred at room temperature for4 h. Water (20 mL) was added and the phases were separated. The aqueousphase was extracted with dichloromethane (2×). The combined organicphases were washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was passed through ashort pad of silica gel eluting with dichloromethane/methanol (95:5).The appropriate fractions were combined and concentrated under reducedpressure. The crude product was further purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm,5 um; mobile phase: Water (0.05% NH₄OH) and CH₃CN (18% CH₃CN up to 50%in 6 min); Detector, UV 254/220 nm to afford 11.1 mg (9%) of1-[4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]-3-[(methylcarbamoyl)amino]-1H-pyrazole-4-carboxamide as a white solid. LC/MS (Method D,ESI): [M+H]⁺=388, R_(T)=1.89 min; ¹H NMR (400 MHz, CD₃OD): δ (ppm) 8.46(s, 1H), 3.16-3.05 (m, 4H), 2.93-2.90 (m, 5H), 2.59-2.54 (m, 4H),2.24-2.17 (m, 2H).

Example 4 (General Procedure C)

Methyl(4-carbamoyl-1-(4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamate

To a solution of3-amino-1-[4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamide(100 mg, 0.303 mmol) in dichloromethane (15 mL) and DIPEA (78.3 mg,0.606 mmol) was added methyl chloroformate (42.9 mg, 0.454 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 12h. The resulting mixture was partitioned between dichloromethane andwater. The organic phase was washed with brine, dried over anhydroussodium sulfate and concentrated under reduced pressure. The residue waspassed through a short pad of silica gel eluting withdichloromethane/methanol (95/5). The crude product was further purifiedby Prep-HPLC with the following conditions: Column, XBridge Shield RP 18OBD Column, 19*150 mm, 5 um; mobile phase, Water (0.05% NH₄OH) and CH₃CN(35% CH₃CN up to 38% in 9 min); Detector, UV 254/220 nm to give 52.7 mg(45%) of methylN-[4-carbamoyl-1-[4-(cyanomethyl)-1-(2,2,2-trifluoroethyl)-piperidin-4-yl]-1H-pyrazol-3-yl]carbamateas a white solid. LC/MS (Method E, ESI): [M+H]⁺=389, R_(T)=1.27 min; ¹HNMR (300 MHz, CD₃OD): δ (ppm) 8.43 (s, 1H), 3.79 (s, 3H), 3.13 (s, 2H),3.06 (q, J=9.9 Hz, 2H), 2.90-2.84 (m, 2H), 2.62-2.48 (m, 4H), 2.21-2.13(m, 2H).

Example 5 (General Procedure D)

1-(7-(Cyanomethyl)-2-oxaspiro[3.5]nonan-7-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of diethyl (cyanomethyl)phosphonate (303 mg, 1.71 mmol) intetrahydrofuran (7.0 mL) was added sodium hydride (40.0 mg, 60%dispersion in mineral oil, 1.00 mmol) under nitrogen at roomtemperature. The reaction mixture was stirred for 2 h at roomtemperature. Then 2-oxaspiro[3.5]nonan-7-one (200 mg, 1.43 mmol) wasadded. The resulting solution was stirred for 12 h at 25° C., andquenched with water. The resulting solution was extracted withdichloromethane (3×) and the organic layers combined and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (100/3) to 190 mg of2-[2-oxaspiro[3.5]nonan-7-ylidene]acetonitrile as a white solid. TLC:R_(f)=0.4; ethyl acetate/hexane=1/4.

To a solution of 2-[2-oxaspiro[3.5]nonan-7-ylidene]acetonitrile (190 mg,1.16 mmol,) in CH₃CN (4.0 mL) was added DBU (354 mg, 2.33 mmol) and3-amino-1H-pyrazole-4-carboxamide (150 mg, 1.19 mmol). The reactionmixture was stirred for 12 h at 50° C., and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (10/1) to afford 160 mg (50%) of3-amino-1-[7-(cyanomethyl)-2-oxaspiro[3.5]nonan-7-yl]-1H-pyrazole-4-carboxamideas a white solid. TLC: R_(f)=0.5; DCM/MeOH=10/1.

To a solution of3-amino-1-[7-(cyanomethyl)-2-oxaspiro[3.5]nonan-7-yl]-1H-pyrazole-4-carboxamide(160 mg, 0.553 mmol) and DIPEA (143 mg, 1.11 mmol) in dichloromethane(5.0 mL) was added dropwise cyclopropanecarbonyl chloride (64.0 mg,0.612 mmol) at 0° C. The resulting solution was stirred for 12 h at 25°C., and concentrated under reduced pressure. The residue was passedthrough a short pad of silica gel eluting with dichloromethane/methanol(10/1). The appropriate fractions were combined and concentrated underreduced pressure. The crude product (160 mg) was further purified byPrep-HPLC with the following conditions: Column, Xbridge Phenyl OBDColumn, 19*150 mm, 5 um; mobile phase, Water (0.05% NH₄OH) and CH₃CN (5%CH₃CN up to 35% in 8 min); Detector, UV 220 nm to afford 98.2 mg of1-(7-(cyanomethyl)-2-oxaspiro[3.5]nonan-7-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method A, ESI): [M+H]⁺=358, R_(T)=1.20 min; ¹HNMR (300 MHz, DMSO-d₆): δ (ppm) 10.13 (s, 1H), 8.45 (s, 1H), 7.50 (s,1H), 7.21 (s, 1H), 4.33 (s, 2H), 4.18 (s, 2H), 3.02 (s, 2H), 2.32-2.28(m, 2H), 1.96-1.78 (m, 5H), 1.52-1.45 (m, 2H), 0.81-0.79 (m, 4H).

Example 6 (General Procedure E)

1-(1-([1,1′-Biphenyl]-4-ylmethyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of3-amino-1-[4-(cyanomethyl)piperidin-4-yl]-1H-pyrazole-4-carboxamide(10.0 g, 40.3 mmol) and DIPEA (7.41 g, 57.4 mmol) in dichloromethane(200 mL) at 0° C. was added dropwise cyclopropanecarbonyl chloride (4.48g, 42.9 mmol). The resulting solution was stirred for 2 days at roomtemperature, and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1)) to afford 12.4 g (74%) of tert-butyl4-(4-carbamoyl-3-(cyclopropanecarboxamido)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylateas a yellow solid. TLC: R_(f)=0.6; DCM/MeOH=10/1.

To a solution of tert-butyl4-(4-carbamoyl-3-(cyclopropanecarboxamido)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate(12.1 g, 29.1 mmol) in dioxane (150 mL) was added 4N HCl in dioxanesolution (40 mL). The resulting solution was stirred for 6 h at roomtemperature. The precipitates were collected by filtration. The filtratewas concentrated under reduced pressure to afford an additional crop ofproduct. The solids were combined and dried under reduced pressure toafford 11.4 g of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride as a white solid. LC/MS (Method G, ESI): [M+H]⁺=317,R_(T)=0.52 min.

To a mixture of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride salt (100 mg, 0.283 mmol) in dichloromethane (3.0 mL) wasadded 4-phenylbenzaldehyde (103 mg, 0.565 mmol) and NaOAc (23.0 mg,0.280 mmol). The mixture was stirred at room temperature for 1 h, andthen NaBH(OAc)₃ (120 mg, 0.566 mmol) was added. The resulting solutionwas stirred overnight at room temperature, and concentrated underreduced pressure. The residue was passed through a short pad of silicagel eluting with EtOAc/THF (85/15). The appropriate fractions werecombined and concentrated under reduced pressure. The crude product (50mg) was further purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile phase,10 mM NH₄HCO₃ solution and CH₃CN (23% CH₃CN up to 45% in 8 min);Detector, UV 254 nm to afford 10.5 mg of1-(1-([1,1′-biphenyl]-4-ylmethyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method E, ESI): [M+H]⁺=483, R_(T)=1.66 min. ¹HNMR (400 MHz, CD₃OD): δ (ppm) 8.46 (s, 1H), 7.65-7.55 (m, 4H), 7.46-7.41(m, 4H), 7.34 (m, 1H), 3.55 (s, 2H), 3.14 (s, 2H), 2.78-2.75 (m, 2H),2.63-2.60 (m, 2H), 2.29-2.20 (m, 2H), 2.17-2.14 (m, 2H), 1.90-1.70 (m,1H), 1.04-1.00 (m, 2H), 0.98-0.94 (m, 2H).

Examples 7 & 8 (General Procedure F)

1-((1S,4S)-1-(Cyanomethyl)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide&1-((1R,4R)-1-(cyanomethyl)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(200 mg, 0.607 mmol) in dichloromethane (10 mL) was added3-(trifluoromethyl)azetidine hydrochloride (118 mg, 0.730 mmol) andNaOAc (49.8 mg, 0.607 mmol). The mixture was stirred at room temperaturefor 1 h, and then NaBH(OAc)₃ (258 mg, 1.22 mmol) was added. Theresulting solution was stirred for 4 h at room temperature and water wasadded. The resulting solution was extracted with ethyl acetate (3×) andthe organic layers combined. The organic phases were washed with ofwater and brine, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was passed through a short pad ofsilica gel eluting with dichloromethane/methanol (95/5). The crudeproduct (120 mg) was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um;mobile phase: 10 mM NH₄HCO₃ solution and CH₃CN (22% CH₃CN up to 46% in 9min); Detector, UV 254 nm to give two fractions. Absolute configurationwas arbitrarily assigned to each diastereomer:

Example 7: the first fraction, 36.7 mg as an off-white solid, LC/MS(Method E, ESI): [M+H]⁺=439, R_(T)=1.31 min, ¹H NMR (400 MHz, CD₃OD): δ(ppm) 8.45 (s, 1H), 3.59-3.46 (m, 2H), 3.29-3.15 (m, 3H), 3.04 (s, 2H),2.75 (m, 2H), 2.35-2.30 (m, 1H), 1.96-1.78 (m, 5H), 1.15-0.98 (m, 4H),0.96-0.92 (m, 2H).

Example 8: the second fraction, 19.3 mg as a white solid, LC/MS (MethodD, ESI): [M+H]⁺=439, R_(T)=2.16 min, ¹H NMR (400 MHz, CD₃OD): δ (ppm)8.40 (s, 1H), 3.56-3.50 (m, 2H), 3.30-3.24 (m, 3H), 3.16 (s, 2H),2.33-2.28 (m, 3H), 2.20-2.14 (m, 2H), 1.90-1.70 (m, 1H), 1.69-1.64 (m,2H), 1.47-1.41 (m, 2H), 1.04-1.00 (m, 2H), 0.98-0.92 (m, 2H).

Examples 9 & 10 (General Procedure G)

1-((1S,4S)-1-(Cyanomethyl)-4-(3-ethoxy-3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide&1-((1R,4R)-1-(cyanomethyl)-4-(3-ethoxy-3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of tert-butyl3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate (250 mg, 1.04 mmol)in N,N-dimethylformamide (10 mL) was added sodium hydride (104 mg, 60%dispersion in mineral oil, 2.59 mmol). The resulting solution wasstirred for 20 min at 0° C., and then iodoethane (809 mg, 5.19 mmol) wasadded dropwise under nitrogen. The resulting solution was stirred for 3h at room temperature, and poured into water (20 mL), extracted withethyl acetate (3×). The organic extracts were combined and washedsuccessively with water and brine, dried over anhydrous sodium sulfateand concentrated under reduced pressure to afford 183 mg (66%) oftert-butyl 3-ethoxy-3-(trifluoromethyl)azetidine-1-carboxylate as ayellow solid.

To a solution of tert-butyl3-ethoxy-3-(trifluoromethyl)azetidine-1-carboxylate (180 mg, 0.668 mmol)in dichloromethane (5.0 mL) was added trifluoroacetic acid (8.0 mL). Theresulting solution was stirred for 4 h at room temperature andconcentrated under reduced pressure. This resulted in 169 mg (crude) of3-ethoxy-3-(trifluoromethyl)azetidine TFA salt as a light yellow solid,which was used without further purification.

To a solution of1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(160 mg, 0.486 mmol) in dichloromethane (8.0 mL) was added3-ethoxy-3-(trifluoromethyl)azetidine TFA salt (98.6 mg) and NaOAc (39.9mg, 0.486 mmol). The solution was stirred for 2 h at room temperature,and then NaBH(OAc)₃ (206 mg, 0.973 mmol) was added. The reaction mixturewas stirred overnight at room temperature, and then partitioned betweenwater and ethyl acetate. Phases were separated. The aqueous phase wasextracted with ethyl acetate (2×). The organic phases were combined andwashed successively with water and brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue was passedthrough a short pad of silica gel eluting with dichloro-methane/methanol(95/5). The crude product (120 mg) was further purified by Prep-HPLCwith the following conditions: Column, XBridge Shield RP18 OBD Column,19*150 mm, 5 um; mobile phase: Water (0.05% NH₄OH) and CH₃CN (40% CH₃CNup to 90% in 9 min); Detector, UV 220 nm to afford two fractions.Absolute configuration was arbitrarily assigned to each diastereomer:

Example 9: the first fraction, 19.6 mg as a white solid, LC/MS (MethodF, ESI): [M+H]⁺=483, R_(T)=1.19 min, ¹H NMR (400 MHz, CD₃OD): δ (ppm)8.44 (s, 1H), 3.67 (q, J=6.8 Hz, 2H), 3.52 (d, J=9.8 Hz, 2H, AB), 3.40(d, J=9.8 Hz, 2H, AB), 3.04 (s, 2H), 2.75 (m, 2H), 2.38-2.32 (m, 1H),1.90-1.78 (m, 5H), 1.23 (t, J=6.8 Hz, 3H), 1.14-1.01 (m, 2H), 1.00-0.98(m, 2H), 0.96-0.91 (m, 2H).

Example 10: the second fraction, 20.6 mg as a white solid, LC/MS (MethodF, ESI): [M+H]⁺=483, R_(T)=1.22 min; ¹H NMR (400 MHz, CD₃OD): δ (ppm)8.40 (s, 1H), 3.72 (q, J=6.8 Hz, 2H), 3.55 (d, J=9.4 Hz, 2H, AB), 3.40(d, J=9.4 Hz, 2H, AB), 3.15 (s, 2H), 2.39-2.29 (m, 3H), 2.19-2.17 (m,2H), 1.94-1.60 (m, 3H), 1.49-1.47 (m, 2H), 1.25 (t, J=6.8 Hz, 3H),1.04-0.93 (m, 4H).

Example 11 (General Procedure H)

1-(4-(Cyanomethyl)-1-((2-hydroxy-[1,1′-biphenyl]-4-yl)methyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a mixture of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride (300 mg, 0.850 mmol) in dichloromethane (8.0 mL) was added4-bromo-3-hydroxybenzaldehyde (341 mg, 1.70 mmol) and NaOAc (69.9 mg,0.852 mmol). The mixture was stirred for 2 h, then NaBH(OAc)₃ (361 mg,1.71 mmol) was added. The resulting solution was stirred overnight atroom temperature, and partitioned between ethyl acetate and water. Theaqueous phase was extracted with ethyl acetate (2×). The combinedorganic phases were washed with water and brine successively, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (95/5). The appropriate fractions were combinedand concentrated under reduced pressure to afford 310 mg (73%) of1-(1-(4-bromo-3-hydroxybenzyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid.

To a solution of1-(1-(4-bromo-3-hydroxybenzyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(100 mg, 0.199 mmol) in dioxane (5.0 mL) was added phenylboronic acid(36.6 mg, 0.300 mmol), Pd(dppf)Cl₂ (14.6 mg, 0.0200 mmol), potassiumcarbonate (55.2 mg, 0.399 mmol) and water (0.50 mL) under nitrogen. Thereaction mixture was stirred for 2 h at 80° C., allowed to cool to roomtemperature and poured into water (10 mL). The resulting solution wasextracted with ethyl acetate (3×). The combined organic phases werewashed with water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was passed through ashort pad of silica gel eluting with dichloromethane/methanol (95/5).The crude product was purified by Prep-HPLC with the followingconditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um;mobile phase: Water (0.05% NH₄OH) and CH₃CN (20% CH₃CN up to 50% in 6min); Detector, UV 220 nm to afford 10.2 mg (10%) of1-(4-(cyanomethyl)-1-((2-hydroxy-[1,1′-biphenyl]-4-yl)methyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method C, ESI): [M+H]⁺=499, R_(T)=1.49 min; ¹HNMR (300 MHz, CD₃OD): δ (ppm) 8.45 (s, 1H), 7.54-7.51 (m, 2H), 7.39-7.34(m, 2H), 7.29-7.21 (m, 1H), 7.19 (d, J=7.8 Hz, 1H), 6.87-6.84 (m, 2H),3.45 (s, 2H), 3.12 (s, 2H), 2.76-2.73 (m, 2H), 2.62-2.58 (m, 2H),2.26-2.12 (m, 4H), 1.90-1.65 (m, 1H), 1.03-0.91 (m, 4H).

Examples 12, 13, 14 & 15 (General Procedure I)

1-((3S,4R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide;1-((3S,4S)-1-([1,1′-biphenyl]-4-ylmethyl)-4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide;1-((3R,4R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide&1-((3R,4S)-1-([1,1′-biphenyl]-4-ylmethyl)-4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of diethyl (cyanomethyl)phosphonate (44.9 g, 253 mmol) intetrahydrofuran (500 mL) was added sodium hydride (18.3 g, 60%dispersion in mineral oil, 275 mmol) in several batches at 0-10° C. Theresulting solution was stirred for 1 h at room temperature and thentert-butyl 3-fluoro-4-oxopiperidine-1-carboxylate (50.0 g, 230 mmol) wasadded. The resulting solution was stirred for 1 h at room temperature.Water (300 mL) was added. The resulting solution was extracted withethyl acetate (3×) and the organic layers combined. The organic phaseswere washed with brine (200 mL), dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was triturated inhexane, and the solid was collected by filtration and dried underreduced pressure to afford 44.0 g (80%) of tert-butyl(4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate as a yellowsolid. LC/MS (Method G, ESI): [M+H]⁺=241, R_(T)=0.87 min & 0.94 min.

To a solution of tert-butyl(4Z)-4-(cyanomethylidene)-3-fluoropiperidine-1-carboxylate (22.9 g, 95.1mmol) in CH₃CN (100 mL) was added 3-amino-1H-pyrazole-4-carboxamide(10.0 g, 79.3 mmol) and DBU (24.1 g, 159 mmol). The reaction mixture wasstirred for 3 days at room temperature and concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/ethyl acetate (100/70). The appropriatefractions were combined and concentrated under reduced pressure toafford 7.01 g (24%) of tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylateas a yellow solid. LC/MS (Method F, ESI): [M+H]⁺=367, R_(T)=1.12 min &1.19 min.

Cyclopropanecarbonyl chloride (500 mg, 4.78 mmol) was added dropwise toa solution of tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate(500 mg, 1.37 mmol) and DIPEA (800 mg, 6.19 mmol) in dichloromethane (50mL) at 0-10° C. The resulting solution was stirred for 2 h at roomtemperature and then quenched by the addition of 20 mL of water. Phaseswere separated. The aqueous phase was extracted with dichloromethane(3×). The combined organic layers were washed with water and brinesuccessively, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with dichloromethane/methanol (100/5). Theappropriate fractions were combined and concentrated under reducedpressure to 500 mg (84%) of tert-butyl4-(4-carbamoyl-3-cyclopropaneamido-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylateas a yellow solid. LC/MS (Method F, ESI): [M+H]⁺=435, R_(T)=1.25 min &1.30 min.

A solution of tert-butyl4-(4-carbamoyl-3-cyclopropaneamido-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate(200 mg, 0.460 mmol) in 4N HCl in dioxane (10 mL) was stirred for 3 h atroom temperature. The reaction mixture was then concentrated underreduced pressure to afford 200 mg of1-(4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride as a yellow solid. LC/MS (Method I, ESI): [M+H]⁺=335,R_(T)=0.87 min.

To a mixture of above crude1-(4-(cyanomethyl)-3-fluoropiperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride (200 mg) in dichloromethane (20 mL) was added4-phenylbenzaldehyde (125 mg, 0.688 mmol) and NaOAc (112 mg, 1.38 mmol).The mixture was stirred for 4 h at 30° C., allowed to cool to roomtemperature and NaBH(OAc)₃ (292 mg, 1.38 mmol) was added. The resultingsolution was stirred overnight at room temperature, and then quenched bythe addition of 100 ml of saturated sodium bicarbonate solution. Theresulting solution was extracted with ethyl acetate (3×). The organiclayers were combined, washed with brine, dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with tetrahydrofuran/ethyl acetate(1:3). The appropriate fractions were combined and concentrated underreduced pressure. The racemic mixtures were separated by chiral-HPLCwith following condition: Column: CHIRAL ART Cellulose-SB, 250*20 mm;Mobile Phase A: Hexane, Mobile Phase B: EtOH; Flow rate: 20 mL/min;Gradient: 20% B in 25 min; 254/220 nm to afford 4 isomers. Absoluteconfiguration was arbitrarily assigned to each stereoisomer:

Example 12: RT₁: 16.76 min; the first fraction, 12.9 mg as a whitesolid, LC/MS (Method A, ESI): [M+H]⁺=501, R_(T)=1.49 min; ¹H NMR (400MHz, CD₃OD): δ (ppm) 8.40 (s, 1H), 7.51-7.46 (m, 4H), 7.34-7.29 (m, 4H),7.22 (t, J=7.4 Hz, 1H), 5.39-5.28 (m, 1H), 3.50 (d, J=13.2 Hz, 1H, AB),3.45 (d, J=13.2 Hz, 1H, AB), 3.25 (d, J=17.2 Hz, 1H, AB), 3.08 (d,J=17.2 Hz, 1H, AB), 2.95-2.75 (m, 1H), 2.72-2.70 (m, 1H), 2.49-2.46 (m,1H), 2.33-2.15 (m, 3H), 1.77-1.64 (m, 1H), 0.92-0.78 (m, 4H).

Example 13: RT₂: 18.54 min, the second fraction, 7.9 mg as a whitesolid. LC/MS (Method A, ESI): [M+H]⁺=501, R_(T)=1.49 min; ¹H NMR (400MHz, CD₃OD): δ (ppm) 8.30 (s, 1H), 7.50 (m, 4H), 7.34-7.31 (m, 4H), 7.22(t, J=7.2 Hz, 1H), 5.24-4.92 (m, 1H), 3.59 (d, J=12.8 Hz, 1H, AB), 3.54(d, J=12.8 Hz, 1H, AB), 3.49-3.43 (m, 1H), 3.21-3.10 (m, 1H), 2.95-2.91(m, 1H), 2.76-2.47 (m, 4H), 2.11-2.08 (m, 1H), 1.93-1.68 (m, 1H),0.91-0.82 (m, 4H).

Example 14: RT₃: 20.7 min; the third fraction, 8.8 mg as a white solid.LC/MS (Method A, ESI): [M+H]⁺=501, R_(T)=1.49 min; ¹H NMR (400 MHz,CD₃OD): δ (ppm) 8.30 (s, 1H), 7.50 (m, 4H), 7.39-7.31 (m, 4H), 7.22 (t,J=7.2 Hz, 1H), 5.03-4.92 (m, 1H), 3.60 (d, J=13.2 Hz, 1H, AB), 3.55 (d,J=13.2 Hz, 1H, AB), 3.49 (d, J=16.8 Hz, 1H, AB), 3.19 (d, J=16.8 Hz, 1H,AB), 2.95-2.92 (m, 1H), 2.77-2.48 (m, 4H), 2.12-2.09 (m, 1H), 1.93-1.51(m, 1H), 0.91-0.78 (m, 4H).

Example 15: RT₄: 23.36 min, the fourth fraction, 15 mg as a white solid.LC/MS (Method A, ESI): [M+H]⁺=501, R_(T)=1.49 min; ¹H NMR (400 MHz,CD₃OD): δ (ppm) 8.40 (s, 1H), 7.49 (m, 4H), 7.34-7.29 (m, 4H), 7.22 (t,J=7.4 Hz, 1H), 5.40-5.28 (m, 1H), 3.51 (d, J=12.8 Hz, 1H, AB), 3.46 (d,J=12.8 Hz, 1H, AB), 3.25 (d, J=17.2 Hz, 1H, AB), 3.08 (d, J=17.2 Hz, 1H,AB), 2.95-2.88 (m, 1H), 2.72-2.71 (m, 1H), 2.49-2.46 (m, 1H), 2.34-2.24(m, 3H), 1.93-1.70 (m, 1H), 0.92-0.91 (m, 2H), 0.90-0.78 (m, 2H).

Example 16 (General Procedure J)

1-(1-((6-(5-Chlorothiophen-3-yl)pyridin-3-yl)methyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a mixture of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride (217 mg, 0.615 mmol) in dichloromethane (8.0 ml) was added6-bromopyridine-3-carbaldehyde (200 mg, 1.08 mmol) and NaOAc (46.6 mg,0.568 mmol). The reaction mixture was stirred for 1 h at roomtemperature and then NaBH(OAc)₃ (241 mg, 1.14 mmol) was added. Theresulting reaction mixture was stirred overnight at room temperature.Water (10 mL) was added. Phases were separated. The aqueous phase wasextracted with ethyl acetate (2×). The organic layers were combined,water and brine successively, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue purified by flashchromatography on silica gel eluting with dichloromethane/methanol(85/15). The appropriate fractions were combined and concentrated underreduced pressure to afford 182 mg (61%) of1-(1-((6-bromopyridin-3-yl)methyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid.

To a solution of1-(1-((6-bromopyridin-3-yl)methyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(100 mg, 0.173 mmol) in dioxane (8.0 mL) was added2-(5-chlorothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (151mg, 0.617 mmol), Pd(dppf)Cl₂ (15.1 mg, 0.0206 mmol), potassium carbonate(56.9 mg, 0.412 mmol) and water (0.30 mL) under nitrogen. The reactionmixture was stirred overnight at 80° C., and allowed to cool to roomtemperature. Water (10 mL) was added. The resulting solution wasextracted ethyl acetate (3×). The organic layers were combined, washedwith water and brine successively, dried over anhydrous sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(90/10). The appropriate fractions were combined and concentrated underreduced pressure to afford 42.2 mg (46%) of1-(1-((6-(5-chlorothiophen-3-yl)pyridin-3-yl)methyl)-4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method F, ESI): [M+H]⁺=524, R_(T)=1.47 min; ¹HNMR (400 MHz, CD₃OD): δ (ppm) 8.49 (s, 1H), 8.45 (s, 1H), 7.86-7.82 (m,2H), 7.76 (d, J=8.0 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 3.57 (s, 2H), 3.14(s, 2H), 2.76 (m, 2H), 2.62 (m, 2H), 2.29-2.20 (m, 2H), 2.19-2.05 (m,2H), 1.90-1.70 (m, 1H), 1.04-0.98 (m, 2H), 0.97-0.92 (m, 2H).

Example 17 (General Procedure K)

Cyclopropylmethyl4-(4-carbamoyl-3-(cyclopropanecarboxamido)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate

To a solution of cyclopropylmethanol (1.00 g, 13.8 mmol) and pyridine(1.32 g, 16.6 mmol) in dichloromethane (30 mL) was added dropwise4-nitrophenyl chloroformate (1.68 g, 8.33 mmol) at 0° C. under nitrogen.The resulting solution was stirred overnight at room temperature. Water(10 mL) was added. The resulting mixture was then washed with 10 ml ofbrine. The organic mixture was dried over anhydrous sodium sulfate andthe solid was filtered out. The organic mixture was concentrated underreduced pressure. The crude product was purified by re-crystallizationfrom n-hexane. This resulted in 1.20 g (36%) of cyclopropylmethyl4-nitrophenyl carbonate as a white solid. TLC: R_(f)=0.5; Hex/EA=4/1.

To solution of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(100 mg, 0.316 mmol) and triethylamine (95.9 mg, 0.948 mmol) in ethanol(30 mL) was added cyclopropylmethyl 4-nitrophenyl carbonate (74.9 mg,0.316 mmol). The resulting solution was stirred for 12 h at roomtemperature, and concentrated under reduced pressure. The residue waspartitioned between dichloromethane and water. Phases were separated.The organic phase was washed with brine, dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The residue was passedthrough a short pad of silica gel eluting with dichloromethane/methanol(93:7). The appropriate fractions were collected and concentrated. Thecrude product was purified by Prep-HPLC with the following conditions:XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile phase: Water(0.05% NH₄OH) and CH₃CN (18% CH₃CN to 50.0% in 6 min); Detector, UV254/220 nm to afford 48.5 mg (37%) of cyclopropylmethyl4-(4-carbamoyl-3-(cyclopropanecarboxamido)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylateas a white solid. LC/MS (Method E, ESI): [M+H]⁺=415, R_(T)=1.31 min; ¹HNMR (300 MHz, CD₃OD): δ (ppm) 8.47 (s, 1H), 3.94-3.90 (m, 4H), 3.15-3.08(m, 4H), 2.63-2.58 (m, 2H), 2.10-2.01 (m, 2H), 1.94-1.80 (m, 1H),1.19-1.11 (m, 1H), 1.04-0.98 (m, 2H), 0.97-0.90 (m, 2H), 0.59-0.53 (m,2H), 0.32-0.27 (m, 2H).

Example 18 (General Procedure L)

1-(4-(Cyanomethyl)-1-(2-phenylacetyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(100 mg, 0.316 mmol) and diisopropylethylamine (109 mg, 0.843 mmol) indichloromethane (5 mL) was added dropwise 2-phenylacetyl chloride (79.0mg, 0.511 mmol) at 0° C. The resulting solution was allowed to warm toroom temperature and stirred for 6 h. The resulting mixture wasconcentrated under reduced pressure. The residue was passed through ashort pad of silica gel eluting with ethyl acetate:THF (85:15). Theappropriate fractions were combined and concentrated under reducedpressure. The residue was further purified by Prep-HPLC with thefollowing conditions: XBridge Shield RP18 OBD Column, 19*150 mm, 5 um;mobile phase, 10 mM NH₄HCO₃ aqueous solution and CH₃CN (23% CH₃CN up to45% in 12 min); Detector, UV 254 nm to afford 4.70 mg of1-(4-(cyanomethyl)-1-(2-phenylacetyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method E, ESI): [M+H]⁺=435, R_(T)=1.22 min. ¹HNMR (400 MHz, CD₃OD): δ (ppm) 8.31 (s, 1H), 7.24-7.21 (m, 2H), 7.16-7.14(m, 3H), 4.16 (d, J=13.6 Hz, 1H), 3.74 (d, J=15.2 Hz, 1H), 3.71 (s, 2H),3.22-2.90 (m, 4H), 2.52-2.40 (m, 2H), 1.95-1.85 (m, 1H), 1.73-1.67 (m,2H), 0.92-0.88 (m, 2H), 0.85-0.81 (m, 2H).

Examples 19 & 20 (General Procedure M)

1-(4-(Cyanomethyl)-1-(2-hydroxy-1-phenylethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide&1-(4-(cyanomethyl)-1-(2-hydroxy-2-phenylethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(100 mg, 0.316 mmol) in acetonitrile (15 mL) was added 2-phenyloxirane(34.0 mg, 0.283 mmol), lithium perchlorate (30.0 mg, 0.282 mmol) andDIPEA (36.0 mg, 0.279 mmol). The reaction mixture was stirred for 16 hat room temperature and concentrated under reduced pressure. The residuewas passed through a short pad of silica gel eluting with ethylacetate:THF (85:15). The appropriate fractions were combined andconcentrated under reduced pressure. The residue was further purified byPrep-HPLC with the following conditions: XBridge Prep C18 OBD Column,19*150 mm, 5 um; mobile phase, 10 mM NH₄HCO₃ aqueous solution and CH₃CN(7% CH₃CN up to 39% in 7 min); Detector, UV 254 nm to afford twofractions:

Example 19: The first fraction (8.3 mg) as a white solid, LC/MS (MethodE, ESI): [M+H]⁺=437, R_(T)=1.16 min. ¹H NMR (400 MHz, CD₃OD): δ (ppm)8.39 (s, 1H), 7.35-7.27 (m, 5H), 3.97-3.92 (m, 1H), 3.82-3.78 (m, 1H),3.47-3.44 (m, 1H), 3.07 (s, 2H), 2.90-2.80 (m, 1H), 2.68-2.66 (m, 1H),2.60-2.52 (m, 2H), 2.40-2.30 (m, 1H), 2.25-2.05 (m, 3H), 1.85-1.75 (m,1H), 1.03-0.99 (m, 2H), 0.96-0.91 (m, 2H).

Example 20: The second fraction (10.5 mg) as a white solid. LC/MS(Method D, ESI): [M+H]⁺=437, R_(T)=1.91 min. ¹H NMR (400 MHz, CD₃OD):δ(ppm) 8.47 (s, 1H), 7.39-7.31 (m, 4H), 7.28-7.24 (m, 1H), 4.82 (dd,J=9.2, 3.6 Hz, 1H), 3.15 (s, 2H), 2.91-2.89 (m, 1H), 2.83-2.80 (m, 1H),2.66-2.60 (m, 3H), 2.50-2.43 (m, 2H), 2.34-2.25 (m, 1H), 2.23-2.17 (m,2H), 1.85-1.70 (m, 1H), 1.04-1.00 (m, 2H), 0.97-0.92 (m, 2H).

Example 21 (General Procedure N)

4-(4-Carbamoyl-3-(cyclopropanecarboxamido)-1H-pyrazol-1-yl)-4-(cyanomethyl)-N-(3,3-difluorocyclobutyl)piperidine-1-carboxamide

A solution of1-[4-(cyanomethyl)-4-piperidyl]-3-(cyclopropanecarbonylamino)-pyrazole-4-carboxamide(25.0 mg, 0.0790 mmol), carbonyldiimidazole (14.1 mg, 0.0869 mmol),1-methyl-2-pyrrolidinone (0.395 mL), and N,N-diisopropylethylamine(0.206 mL, 1.19 mmol) was stirred for 1 hr at room temperature.3,3-difluorocyclobutanamine hydrochloride (113 mg, 0.790 mmol) wasadded, and the reaction was stirred at 80° C. for 16 hours. The mixturewas purified directly and was purified by reverse phase chromatography((20-60% acetonitrile: 0.10% aqueous NH₄OH solution in 15 min), yielding4-[4-carbamoyl-3-(cyclopropanecarbonyl-amino)pyrazol-1-yl]-4-(cyanomethyl)-N-(3,3-difluorocyclobutyl)piperidine-1-carboxamide(3.8 mg, 11%) as a white solid. LC/MS (Method J, ESI): [M+H]⁺=450,R_(T)=3.25 min. ¹H NMR (400 MHz, DMSO-d₆): δ 10.15 (s, 1H), 8.48 (s,1H), 7.47 (s, 1H), 7.23 (s, 1H), 6.91 (d, J=6.5 Hz, 1H), 4.03-3.86 (m,1H), 3.75-3.58 (m, 2H), 3.13 (s, 2H), 3.01-2.87 (m, 2H), 2.87-2.73 (m,2H), 2.69-2.38 (m, 2H), 2.40-2.26 (m, 2H), 1.99-1.82 (m, 2H), 0.94 (d,J=6.9, 5.7 Hz, 1H), 0.80 (d, J=6.4 Hz, 4H).

Example 186 (General Procedure O)

Methyl(4-carbamoyl-1-(4-(cyanomethyl)-1-((2-hydroxy-[1,1′-biphenyl]-4-yl)methyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamate

A solution of tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate(300 mg, 0.861 mmol), DIPEA (222 mg, 1.72 mmol) in dichloromethane (8.00mL) was stirred for 30 min at 0° C. Methyl chloroformate (121 mg, 1.28mmol) was added dropwise to the resulting mixture. The reaction mixturewas allowed to warm to room temperature and stirred for 3 days. Waterwas added and the resulting solution was extracted with ethyl acetate(3×). The combined organic phase was washed with water and brine, driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified by flash chromatography on silica gel elutingwith dichloromethane/methanol (90:10). The appropriate fractions werecombined and concentrated under reduced pressure to afford 164 mg (47%)of tert-butyl4-[4-carbamoyl-3-[(methoxycarbonyl)amino]-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylateas a white solid. TLC: R_(f)=0.4; PE/EA=1/1.

A mixture of tert-butyl4-[4-carbamoyl-3-[(methoxycarbonyl)amino]-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidine-1-carboxylate(164 mg, 0.404 mmol) and HCl/dioxane (4 M, 10 ml) was stirred for 3 h atroom temperature. The resulting mixture was concentrated under reducedpressure to afford the HCl salt of methylN-[4-carbamoyl-1-[4-(cyanomethyl)piperidin-4-yl]-1H-pyrazol-3-yl]carbamate(176 mg) as a white solid.

A mixture of methylN-[4-carbamoyl-1-[4-(cyanomethyl)piperidin-4-yl]-1H-pyrazol-3-yl]carbamateHCl salt (176 mg), 4-bromo-3-hydroxybenzaldehyde (230 mg, 1.14 mmol),NaOAc (47.2 mg, 0.575 mmol), NaBH(OAc)₃ (243 mg, 1.15 mmol) indichlromethane (8 mL) was stirred overnight at room temperature. Waterand ethyl acetate were added and phases were separated. The organiclayer was washed with water and brine, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. The resultantresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (90:10). The appropriate fractions werecombined and concentrated under reduced pressure to afford 169 mg (60%)of methylN-(1-[1-[(4-bromo-3-hydroxyphenyl)methyl]-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl)carbamateas a white solid. TLC: R_(f)=0.4; MeOH/DCM=1/10.

To a 35 mL microwave reaction vessel was placed ethylN-(1-[1-[(4-bromo-3-hydroxyphenyl)methyl]-4-(cyanomethyl)piperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl)carbamate(169 mg, 0.334 mmol), phenylboronic acid (63.1 mg, 0.518 mmol),Pd(dppf)Cl₂ (28.1 mg, 0.0380 mmol,), potassium carbonate (95.2 mg, 0.689mmol), water (1.50 mL) and dioxane (7.00 mL). The reaction vessel wasthen degassed and charged with nitrogen 3 times. The resulting mixturewas heated for 2 h at 80° C. in an oil bath and allowed to cool to roomtemperature. The resulting mixture was diluted with water and extractedwith ethyl acetate (×2). The combined organic phase was washed withwater and brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (90:10). Theappropriate fractions were combined and concentrated under reducedpressure. The crude product was further purified by Prep-HPLC with thefollowing conditions Column: XBridge Prep C18 OBD Column, 5 um, 19*150mm; mobile phase, Water (0.05% NH₃H2O) and ACN (25% ACN up to 40% in 11min); Detector, UV 220, 254 nm to afford 27.5 mg (17%) of methylN-[4-carbamoyl-1-[4-(cyanomethyl)-1-[(3-hydroxy-4-phenylphenyl)methyl]piperidin-4-yl]-1H-pyrazol-3-yl]carbamateas a white solid. LC/MS (Method F, ESI): [M+H]⁺=489.2, R_(T)=1.35. ¹HNMR (400 MHz, CD₃OD): δ (ppm) 8.45 (s, 1H), 7.55 (dd, J=8.4, 1.2 Hz,2H), 7.39 (dd, J=8.4, 7.6 Hz, 2H), 7.31-7.26 (m, 1H), 7.22 (d, J=7.6 Hz,1H), 6.90 (d, J=1.6 Hz, 1H), 6.89 (dd, J=7.6, 1.6 Hz, 1H), 3.80 (s, 3H),3.48 (s, 2H), 3.15 (s, 2H), 2.79-2.76 (m, 2H), 2.63-2.60 (m, 2H),2.29-2.21 (m, 2H), 2.18-2.15 (m, 2H).

Example 210 & 211 (General Method P)

1-(4-([1,1′-Biphenyl]-4-yloxy)-1-(cyanomethyl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

To a solution of1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(500 mg, 1.51 mmol) in tetrahydrofuran (9.0 mL) and ethanol (3.0 mL) wasadded NaBH₄ (115 mg, 3.04 mmol). The resulting solution was stirred for4 h at room temperature. The reaction was then quenched by the additionof water (1.0 mL) and concentrated under reduced pressure. The residuewas partitioned between water and EtOAc. The organic layer was washedwith brine, dried over sodium sulfate, concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (90/10). The appropriate fractionswere combined and concentrated under reduced pressure to afford 475 mg(94%) of1-(1-(cyanomethyl)-4-hydroxycyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a yellow solid. TLC: R_(f)=0.3; PE/EA=1/1.

To a solution of1-(1-(cyanomethyl)-4-hydroxycyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(400 mg, 1.20 mmol) in tetrahydrofuran (20.0 mL) was added4-phenylphenol (308 mg, 1.81 mmol), PPh₃ (475 mg, 1.81 mmol) and DIAD(366 mg, 1.81 mmol). The resulting solution was stirred overnight atroom temperature then concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting withdichloromethane/methanol (97/3). The appropriate fractions were combinedand concentrated under reduced pressure to obtain two fractions with thesame mass ion:

Undesired isomer: 4.60 mg (1%) of1-(4-([1,1′-biphenyl]-4-yloxy)-1-(cyanomethyl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(isomer 1) as a white solid., LC/MS (Method J, ESI): [M+H]⁺=484.4,R_(T)=3.31 min; ¹H NMR (400 MHz, CD₃OD): δ (ppm) 8.52 (s, 1H), 7.56 (dd,J=7.6, 1.6 Hz, 2H), 7.54 (d, J=8.8 Hz, 2H), 7.41 (dd, J=8.0, 7.6 Hz,2H), 7.31-7.27 (m, 1H), 7.02 (d, J=8.8 Hz, 2H), 4.60-4.50 (m, 1H), 3.17(s, 2H), 2.80-2.65 (m, 2H), 2.13-2.05 (m, 4H), 1.95-1.75 (m, 1H),1.68-1.63 (m, 2H), 1.05-1.01 (m, 2H), 0.97-0.93 (m, 2H).

Desired isomer: 10.8 mg (2%) of1-(4-([1,1′-biphenyl]-4-yloxy)-1-(cyanomethyl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(isomer 2) as a white solid. LC/MS (Method K, ESI): [M+H]⁺=484.3,R_(T)=1.90 min; ¹HNMR (400 MHz, CD₃OD): δ (ppm) 8.50 (s, 1H), 7.57 (d,J=8.8 Hz, 2H), 7.59-7.55 (dd, J=8.4, 1.6 Hz, 2H), 7.42 (dd, J=8.4, 7.6Hz, 2H), 7.31-7.27 (m, 1H), 7.07 (d, J=8.8 Hz, 2H), 4.68-4.58 (m, 1H),3.14 (s, 2H), 2.56-2.52 (m, 2H), 2.35-2.29 (m, 2H), 2.04-2.00 (m, 2H),1.95-1.85 (m, 3H), 1.05-0.1.01 (m, 2H), 0.98-0.92 (m, 2H).

Example 248 (General Procedure R)

MethylN-[4-carbamoyl-1-[4-(cyanomethyl)-1-[(2,6-difluoro-3-hydroxy-4-phenylphenyl)methyl]-3-fluoropiperidin-4-yl]-1H-pyrazol-3-yl]carbamate

Racemic tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate(280 g, mixture of 4 isomers) was separated by chiral SFC using thefollowing conditions: Column: CHIRALPAK IA-SFC-02, 5 um, 5 cm*25 cm;Mobile Phase A: CO₂: 60, Mobile Phase B: ethanol: 40; Flow rate: 160mL/min; Detector: 220 nm; R_(T)1=3.74 min (containing two peaks);R_(T2)=4.91 min; R_(T3)=6.65 min. Fractions from the third peak werecollected and evaporated to afford 25.76 g (5.5%) of tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylateas an off-white solid. LC/MS (Method N, ESI): [M+H]⁺=367.2, R_(T)=1.07min. ¹H NMR (300 MHz, CD₃OD): δ (ppm) 8.17 (s, 1H), 5.08-5.01 (m, 1H),4.28-4.20 (m, 2H), 3.42-3.36 (m, 3H), 3.32-3.17 (m, 1H), 2.46-2.42 (m,1H), 2.15-2.10 (m, 1H), 1.46 (s, 9H).

To a solution of single desired isomer tert-butyl4-(3-amino-4-carbamoyl-1H-pyrazol-1-yl)-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate(4.00 g, 10.9 mmol) in dichloromethane (35.0 mL) was added DIPEA (8.40g, 65.0 mmol). The resulting solution was cooled to 0° C. in a water/icebath before dropwise addition of methyl chloroformate (7.60 g, 80.4mmol). The resulting solution was stirred overnight at room temperature.Water (30 mL) was added and the mixture extracted with ethyl acetate(3×20 mL). The combined organic layer was washed with water and brine,dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyeluting with ethyl acetate/petroleum ether (70/30). Appropriatefractions were combined and evaporated to afford 3.9 g (84%) oftert-butyl4-[4-carbamoyl-3-[(methoxycarbonyl)amino]-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylateas a light yellow solid. LC/MS (Method N, ESI): [M+H]⁺=425.2, R_(T)=1.08min.

A solution of tert-butyl4-[4-carbamoyl-3-[(methoxycarbonyl)amino]-1H-pyrazol-1-yl]-4-(cyanomethyl)-3-fluoropiperidine-1-carboxylate(5.00 g, 11.78 mmol,) in HCl/dioxane (4.0 M, 30 ml) was stirred for 4 hat room temperature. The mixture was concentrated under reduced pressureand the resultant residue triturated with ethyl acetate. Theprecipitated solid was collected by filtration to afford 4.30 g of thehydrochloride salt of methylN-[4-carbamoyl-1-[4-(cyanomethyl)-3-fluoropiperidin-4-yl]-1H-pyrazol-3-yl]carbamateas a light yellow solid. LC/MS (Method N, ESI): [M+H]⁺=325.1, R_(T)=0.66min.

To a solution of methylN-4-carbamoyl-1-[4-(cyanomethyl)-3-fluoropiperidin-4-yl]-1H-pyrazol-3-ylcarbamate(320 mg, 0.987 mmol) in dichloromethane (25 mL) was added4-bromo-2,6-difluoro-3-hydroxybenzaldehyde (300 mg, 1.26 mmol), DIPEA(150 mg, 1.16 mmol) and NaBH(OAc)₃ (600 mg, 2.83 mmol). The resultingsolution was stirred overnight at room temperature and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography eluting with petroleum ether/ethyl acetate (50/50). Theappropriate fractions were combined and concentrated under reducedpressure to afford 40 mg (6%) of methylN-(1-[1-[(4-bromo-2,6-difluoro-3-hydroxyphenyl)methyl]-4-(cyanomethyl)-3-fluoropiperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl)carbamateas a white solid. LC/MS (Method N, ESI): [M+H]⁺=545.2, R_(T)=0.93 min.

A degassed mixture of methylN-(1-[1-[(4-bromo-2,6-difluoro-3-hydroxyphenyl)methyl]-4-(cyanomethyl)-3-fluoropiperidin-4-yl]-4-carbamoyl-1H-pyrazol-3-yl)carbamate(20.0 mg, 0.037 mmol), phenylboronic acid (10.0 mg, 0.0820 mmol),Pd(dppf)Cl₂ (3 mg, 0.00367 mmol) and Cs₂CO₃ (24.0 mg, 0.0740 mmol) indioxane (5.0 mL) and water (1.0 mL) was heated for 6 h at 60° C. thenconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(95/5). The appropriate fractions were combined and concentrated underreduced pressure. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Prep C18 OBD Column, 5 um, 19*150mm; mobile phase, Water (0.05% NH₃H2O) and ACN (25% ACN up to 50% in 10min); Detector, UV 220, 254 nm. Appropriate fractions were combined andevaporated to afford 3.90 mg (20%) of methylN-[4-carbamoyl-1-[4-(cyanomethyl)-1-[(2,6-difluoro-3-hydroxy-4-phenylphenyl)methyl]-3-fluoropiperidin-4-yl]-1H-pyrazol-3-yl]carbamateas an off-white solid. LC/MS (Method K, ESI): [M+H]⁺=543.3, R_(T)=1.36min; ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 9.54 (s, 1H), 9.49 (s, 1H), 8.44(s, 1H), 7.63 (s, 1H), 7.60 (dd, J=6.8, 1.6 Hz, 2H), 7.44 (dd, J=8.4,6.8, 2H), 7.39-7.34 (m, 1H), 7.30 (s, 1H), 7.04 (dd, J=10.4, 2.0 Hz,1H), 5.00-4.88 (m, 1H), 3.69 (s, 2H), 3.64 (s, 3H), 3.36-3.33 (m, 1H),3.22 (s, 2H), 2.95-2.80 (m, 2H), 2.75-2.60 (m, 2H), 2.06-2.03 (m, 1H).

Example 262 (General Method Q)

MethylN-[4-carbamoyl-1-[1-(cyanomethyl)-4-[(2-phenylphenyl)amino]cyclohexyl]-1H-pyrazol-3-yl]carbamate

To a solution of3-amino-1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-1H-pyrazole-4-carboxamide(1.00 g, 3.27 mmol) and DIPEA (1.70 g, 13.1 mmol) in dichloromethane (10mL) was added methyl chloroformate (2.45 g, 22.5 mmol) at 0° C. Theresulting solution was stirred for 15 min at 0° C. in a water/ice baththen allowed to warm to room temperature and stirred for 3 h. Thereaction mixture was diluted with water and extracted withdichloromethane (3×). The combined organic phase was washed with brine,dried over sodium sulfate, concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (10/1). The appropriate fractions were combinedand concentrated under reduced pressure to afford 1.82 g of methylN-[4-carbamoyl-1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-1H-pyrazol-3-yl]carbamateas a white solid. TLC: R_(f)=0.4; PE/EA=2/1.

A solution of methylN-[4-carbamoyl-1-[8-(cyanomethyl)-1,4-dioxaspiro-[4.5]decan-8-yl]-1H-pyrazol-3-yl]carbamate(500 mg, 1.38 mmol) in tetrahydrofuran (5 mL) and 3N HCl aqueoussolution (5 mL) was stirred for 3 h at room temperature. The resultingmixture was concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and saturated sodium bicarbonatesolution. The aqueous phase was extracted with ethyl acetate (3×). Thecombined organic layer was washed with brine, dried over sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with dichloromethane/methanol(10/1). The appropriate fractions were combined and concentrated underreduced pressure to afford 150 mg (34%) of methylN-[4-carbamoyl-1-[1-(cyanomethyl)-4-oxocyclohexyl]-1H-pyrazol-3-yl]carbamateas a yellow solid. TLC: R_(f)=0.3; PE/EA=2/1.

To a solution of methylN-[4-carbamoyl-1-[1-(cyanomethyl)-4-oxocyclohexyl]-1H-pyrazol-3-yl]carbamate(300 mg, 0.940 mmol) in dichloromethane (10 mL) was added4-phenylaniline (238 mg, 1.40 mmol), NaOAc (77.1 mg, 0.940 mmol) andNaBH(OAc)₃ (399 mg, 1.88 mmol). The resulting solution was stirred for12 h at room temperature then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting withdichloromethane/methanol (95/5). The appropriate fractions were combinedand concentrated under reduced pressure. The crude product was furtherpurified by Prep-HPLC with the following conditions: Column, XBridgePrep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Waters (0.05%NH₃H2O) and ACN (25% ACN up to 50% in 10 min); Detector, VU 220, 254 nmto afford two fractions with correct mass ion:

Isomer 1: 14.0 mg (3%) of methylN-[4-carbamoyl-1-[1-(cyanomethyl)-4-[(2-phenylphenyl)amino]cyclohexyl]-1H-pyrazol-3-yl]carbamate(isomer1) as a white solid, LC/MS (Method F, ESI): [M+H]⁺=473.3,R_(T)=1.61 min; ¹H NMR (400 MHz, CD₃OD): δ (ppm) 8.52 (s, 1H), 7.52 (dd,J=8.4, 1.2 Hz, 2H), 7.41 (dd, J=6.4, 2.0 Hz, 2H), 7.36 (dd, J=8.4, 7.6Hz, 2H), 7.24-7.20 (m, 1H), 6.73 (dd, J=6.4, 2.0 Hz, 2H), 3.80 (s, 3H),3.50-3.46 (m, 1H), 3.08 (s, 2H), 2.85-2.81 (m, 2H), 2.11-1.96 (m, 4H),1.32-1.23 (m, 2H).

Isomer 2, 1.40 mg of methylN-[4-carbamoyl-1-[1-(cyanomethyl)-4-[(2-phenylphenyl)amino]cyclohexyl]-1H-pyrazol-3-yl]carbamate(isomer2) as a white solid. LC/MS (Method L, ESI): [M+H]⁺=473.3,R_(T)=2.95 min; ¹H NMR (400 MHz, CD₃OD): δ (ppm) 8.44 (s, 1H), 7.54 (dd,J=7.2, 1.6 Hz, 2H), 7.43 (d, J=8.8 Hz, 2H), 7.37 (dd, J=7.6, 7.2 Hz,2H), 7.24-7.20 (m, 1H), 6.77 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.60-3.50(m, 1H), 3.30 (s, 2H), 2.45-2.35 (m, 2H), 2.30-2.20 (m, 2H), 2.05-1.95(m, 2H), 1.70-1.60 (m, 2H).

Example 294 (General Procedure S)

1-(1-(Cyanomethyl)-4-(3-(4-ethynylphenoxy)-3-methylazetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

A mixture of 4-bromophenol (1.74 g, 10.0 mmol) and Ph₃P (2.33 g, 8.88mmol) in toluene (15.0 mL) was heated for 10 min at 50° C. To the heatedreaction mixture was added a solution of1-(diphenylmethyl)-3-methylazetidin-3-ol (1.50 g, 5.92 mmol) and DIAD(1.80 g, 8.90 mmol) in toluene (15 mL). The resulting solution washeated overnight at 95° C., allowed to cool to room temperature andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with ethyl acetate/petroleum ether(1/20). The appropriate fractions were combined and concentrated underreduced pressure to afford 1.10 g (45%) of3-(4-bromophenoxy)-1-(diphenylmethyl)-3-methylazetidine as an off-whitesolid. LC/MS (Method N, ESI): [M+H]⁺'² 408.1; 410.1, R_(T)=1.18 min.

1-Chloroethyl chloroformate (4.25 g, 29.7 mmol) was added to a solutionof 3-(4-bromophenoxy)-1-(diphenylmethyl)-3-methylazetidine (1.10 g,2.694 mmol) in CH₃CN (20.0 mL). The resulting solution was stirred for 5h at 50° C. Methanol (20.0 mL) was added and the mixture stirred for anadditional 2 h at 50° C. The mixture was allowed to cool to ambienttemperature and the solid removed by filtration. The filtrate wasconcentrated under reduced pressure to afford 760 mg of3-(4-bromophenoxy)-3-methylazetidine hydrochloride as a yellow crudesolid. LC/MS (Method N, ESI): [M+H]⁺=242.1; 244.1, R_(T)=0.95 min.

A mixture of of1-(1-(cyanomethyl)-4-oxocyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(500 mg, 1.51 mmol), 3-(4-bromophenoxy)-3-methylazetidine hydrochloride(509 mg, 1.82 mmol) and NaOAc (125 mg, 1.52 mmol) in dichloromethane(40.0 mL) was stirred overnight at room temperature before addition ofNaBH(OAc)₃ (644 mg, 3.03 mmol). The resulting solution was stirred foran additional 4 h at room temperature then concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with dichloromethane/methanol (15/1). The appropriate fractionswere combined and concentrated under reduced pressure to afford 620 mg(74%) of1-(4-(3-(4-bromophenoxy)-3-methylazetidin-1-yl)-1-(cyanomethyl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a light yellow solid. LC/MS (Method N, ESI): [M+H]⁺=555.2 & 557.2,R_(T)=1.02 min.

A degassed mixture of1-(4-(3-(4-bromophenoxy)-3-methylazetidin-1-yl)-1-(cyanomethyl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(300 mg, 0.540 mmol), ethynyltrimethylsilane (529 mg, 5.38 mmol),Pd(OAc)₂ (24.0 mg, 0.107 mmol), P(t-Bu)₃.HBF₄ (63.0 mg, 0.217 mmol), CuI(21.0 mg, 0.110 mmol) and triethylamine (6.00 mL) in DMSO (2.00 mL) washeated for 6 h at 90° C. The reaction was allowed to cool to roomtemperature and quenched by the addition of water (50 mL). The resultingsolution was extracted with ethyl acetate (3×) and the combined organiclayer dried over anhydrous magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol (16/1). Theappropriate fractions were combined and concentrated under reducedpressure to afford 200 mg (65%) of1-(1-(cyanomethyl)-4-(3-methyl-3-(4-((trimethylsilyl)ethynyl)phenoxy)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a brown solid. LC/MS (Method N, ESI): [M+H]⁺=573.4, R_(T)=1.17 min.

A mixture of 1-(1-(cyanomethyl)-4-(3-methyl-3-(4-((trimethylsilyl)-ethynyl)phenoxy)azetidin-1-yl)cyclohexyl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(200 mg, 0.349 mmol) and potassium carbonate (145 mg, 1.04 mmol) inmethanol (10 mL) was stirred for 2 h at room temperature thenconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with dichloromethane/methanol(13/1). The appropriate fractions were combined and concentrated underreduced pressure. The mixture of isomers was separated by Prep-HPLC withthe following conditions: Column, Kinetex EVO C18 Column, 5 um, 30*150mm; mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN (30% ACN up to 40%in 10 min); Detector, UV 254 nm to afford two fractions:

Isomer 1 (first fraction): 24.8 mg (14%) of1-[1-(cyanomethyl)-4-[3-(4-ethynylphenoxy)-3-methylazetidin-1-yl]cyclohexyl]-3-cyclopropane-1H-pyrazole-3,4-diamido as awhite solid. Isomer 1: LC/MS (Method M, ESI): [M+H]⁺=501.3, R_(T)=2.15min. ¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 10.18 (s, 1H), 8.43 (s, 1H),7.53 (s, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.23 (s, 1H), 6.71 (d, J=8.8 Hz,2H), 4.03 (s, 1H), 3.45 (d, J=7.6 Hz, 2H), 3.07 (d, J=7.2 Hz, 2H), 3.01(s, 2H), 2.50-2.45 (m, 3H), 2.15-2.05 (m, 1H), 1.80-1.65 (m, 4H), 1.53(s, 3H), 0.95-0.85 (m, 2H), 0.85-0.75 (m, 4H).

Isomer, 21.4 mg (12%) of1-[1-(cyanomethyl)-4-[3-(4-ethynylphenoxy)-3-methylazetidin-1-yl]cyclohexyl]-3-cyclopropane-1H-pyrazole-3,4-diamidoas a white solid. LC/MS (Method M, ESI): [M+H]⁺=501.3, R_(T)=2.15 min.¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 10.18 (s, 1H), 8.43 (s, 1H), 7.52 (s,1H), 7.38 (d, J=8.4 Hz, 2H), 7.22 (s, 1H), 6.74 (d, J=8.8 Hz, 2H), 4.04(s, 1H), 3.52 (d, J=7.6 Hz, 2H), 3.10 (d, J=7.2 Hz, 2H), 3.09 (s, 2H),2.51-2.50 (m, 1H), 2.25-2.20 (m, 1H), 2.18-2.00 (m, 4H), 1.61 (s, 3H),1.50-1.35 (m, 4H), 1.85-1.75 (m, 4H).

Example 298 (General Procedure T)

Methyl(4-carbamoyl-1-(4-(cyanomethyl)-3-fluoro-1-(4-(prop-1-yn-1-yl)benzyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamate

To a mixture of methyl(4-carbamoyl-1-(4-(cyanomethyl)-3-fluoropiperidin-4-yl)-1H-pyrazol-3-yl)carbamatehydrochloride (180 mg, 0.50 mmol) in 1,2-dichloroethane (3.0 ml) wasadded trimethylamine (0.21 mL, 1.50 mmol) and 4-iodobenzaldehyde (174mg, 0.75 mmol). The reaction mixture was stirred for 10 mins at roomtemperature, and then NaBH(OAc)₃ (423 mg, 1.99 mmol) was added. Theresulting reaction mixture was stirred overnight at room temperature.Water (20 mL) was added and the phases were separated. The aqueous phasewas extracted with dichloromethane (2×). The combined organic layer waswashed with water and brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue purified by flashchromatography on silica gel eluting with dichloromethane/methanol(85/15). The appropriate fractions were combined and concentrated underreduced pressure to afford 105 mg (39%) of methyl(4-carbamoyl-1-(4-(cyanomethyl)-3-fluoro-1-(4-iodobenzyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamateas a white solid. LC/MS (Method P, ESI): [M+H]⁺=541.2, R_(T)=1.14 min.

A degassed solution of methyl(4-carbamoyl-1-(4-(cyanomethyl)-3-fluoro-1-(4-iodobenzyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamate(105 mg, 0.194 mmol), bis(triphenylphosphine)palladium chloride (14 mg,0.019 mmol), tributyl(prop-1-ynyl)stannane (99 mg, 0.292 mmol) inN-methyl-2-pyrrolidone (1 mL) was stirred at 65° C. for 18 h. Themixture was allowed to cool to room temperature; ethyl acetate was addedthe precipitated solid was removed by filtration through celite. Thefiltrate was washed with water and saturated aqueous sodium chloridesolution. The organic phase was dried over magnesium sulfate, filtered,and concentrated. The residue was purified by silica gel chromatographyeluting with 0 to 15% methanol in dichloromethane. Appropriate fractionswere combined and evaporated to afford methyl(4-carbamoyl-1-(4-(cyanomethyl)-3-fluoro-1-(4-(prop-1-yn-1-yl)benzyl)piperidin-4-yl)-1H-pyrazol-3-yl)carbamate(22 mg, 25%) as an orange solid. LC/MS (Method P, ESI): [M+H]⁺=453.3,R_(T)=1.14 min; ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 9.48 (s, 1H), 8.46 (s,1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.40-7.32 (m, 2H), 7.31-7.19 (m, 2H),5.05-4.75 (m, 1H), 3.64 (s, 3H), 3.57 (s, 2H), 3.48-3.38 (m, 1H),3.38-3.31 (m, 1H), 2.87-2.82 (m, 1H), 2.75-2.67 (m, 2H), 2.66-2.49 (m,2H), 2.07-2.00 (m, 1H), 2.03 (s, 3H).

Example 299 (General Procedure U)1-(4-(Cyanomethyl)-1-(4-(cyclopropylethynyl)benzyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide

A mixture of1-(4-(cyanomethyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamidehydrochloride (1.00 g, 2.83 mmol), trimethylamine (1.19 mL, 8.5 mmol)and 4-iodobenzaldehyde (986 mg, 4.25 mmol) in 1,2-dichloroethane (15.0ml) was stirred for 10 mins at room temperature before addition ofNaBH(OAc)₃ (2.40 g, 11.34 mmol). The resulting reaction mixture wasstirred overnight at room temperature. Water (50 mL) was added and themixture was extracted with dichloromethane (3×). The combined organiclayer was washed with water and brine, dried over anhydrous magnesiumsulfate and concentrated under reduced pressure. The residue purified byflash chromatography on silica gel eluting with dichloromethane/methanol(85/15). The appropriate fractions were combined and concentrated underreduced pressure to afford 570 mg (38%) of1-(4-(cyanomethyl)-1-(4-iodobenzyl)-piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method P, ESI): [M+H]⁺=533.1, R_(T)=0.94 min.

A degassed solution of1-(4-(cyanomethyl)-1-(4-iodobenzyl)piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamide(50 mg, 0.094 mmol), bis(triphenylphosphine)palladium chloride (7 mg,0.0094 mmol), copper(I) iodide (2 mg, 0.0094 mmol), ethynylcyclopropane(10 mg, 0.14 mmol) and trimethylamine (0.2 mL, 1.43 mmol) inN-methyl-2-pyrrolidone (0.4 mL) was stirred at 90° C. for 1 h. Themixture was allowed to cool to room temperature, ethyl acetate was addedand the precipitated solid removed by filtration through celite. Thefiltrate was washed with water and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered, and concentrated. Theresidue was purified by silica gel column chromatography eluting with 0to 15% methanol in dichloromethane. Appropriate fractions were combinedand evaporated to afford 30 mg (67%) of1-(4-(cyanomethyl)-1-(4-(cyclopropyl-ethynyl)benzyl)-piperidin-4-yl)-3-(cyclopropanecarboxamido)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method P, ESI): [M+H]⁺=471.2, R_(T)=1.13 min;¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.13 (s, 1H), 8.47 (s, 1H), 7.48 (s,1H), 7.29 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H), 3.40 (s, 2H), 3.17(d, J=5.3 Hz, 0H), 3.06 (s, 2H), 2.60 (d, J=8.8 Hz, 2H), 2.45-2.36 (m,2H), 2.06-1.93 (m, 3H), 1.52 (tt, J=8.3, 5.0 Hz, 1H), 0.92-0.82 (m, 2H),0.86-0.76 (m, 4H), 0.77-0.66 (m, 2H).

Example 301 (General Procedure V)

3-((4-((Difluoromethyl)sulfonyl)phenyl)amino)-1-(4-ethyl-1-(2-fluoro-5-hydroxybenzyl)piperidin-4-yl)-1H-pyrazole-4-carboxamide

To a cooled (0° C.) solution of potassium tert-butoxide (3.55 g, 31.6mmol, 1.05 equiv) in tetrahydrofuran (50 mL) was added2-diethoxyphosphoryl-N-methoxy-N-methyl-acetamide (7.92 g, 33.1 mmol).The reaction mixture was allowed to warm to room temperature over 30mins then stirred for an additional 1 h at room temperature. The mixturewas cooled to −78° C. and a solution of tert-butyl4-oxopiperidine-1-carboxylate (6 g, 30.1 mmol) in tetrahydrofuran (50mL) was added. The mixture was allowed to slowly warm to roomtemperature and allowed to stir for 16 h. Water (250 mL) was added andthe mixture extracted with isopropyl acetate (3×100 mL). The combinedorganic layer was washed with water and brine, dried over sodium sulfateand concentrated under reduced pressure to afford tert-butyl4-[2-[methoxy(methyl)amino]-2-oxo-ethylidene]piperidine-1-carboxylate asa white solid that was used in the next step without furtherpurification.

A suspension of 5-amino-1H-pyrazole-4-carboxamide hemisulfate (6.31 g,36 mmol) and tert-butyl4-[2-[methoxy(methyl)amino]-2-oxo-ethylidene]piperidine-1-carboxylate(8.53 g, 30 mmol) in N,N-dimethylformamide (100 mL) was treated withcesium carbonate (21.5 g, 66 mmol) then stirred 16 h at roomtemperature. The precipitated solid was removed by filtration throughCelite and the filtrate concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel eluting with agradient of 0 to 10% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 600 mg (5%) of tert-butyl4-(3-amino-4-carbamoyl-pyrazol-1-yl)-4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylateas a white solid.

A degassed mixture of tert-butyl4-(3-amino-4-carbamoyl-pyrazol-1-yl)-4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate(600 mg, 1.46 mmol), 1-bromo-4-(difluoromethylsulfonyl)benzene (594 mg,2.19 mmol), potassium phosphate tribasic (640 mg, 2.92 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (32 mg, 0.073mmol, 0.05 equiv) and tris(dibenzylideneacetone)dipalladium(0) (17 mg,0.018 mmol, 0.0125 equiv) in 1,4-dioxane (20 mL) and tert-butyl alcohol(5 mL) was heated for 16 h at 80° C. The mixture was allowed to cool toroom temperature and the precipitated solid removed by filtrationthrough Celite. The filtrate was concentrated under reduced pressure andthe residue was purified by flash chromatography on silica gel elutingwith a gradient of 0 to 5% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 600 mg (68%) of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]pyrazol-1-yl]-4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylateas a white solid.

Diisobutylaluminum hydride (1M in heptane, 10 mL, 10 mmol) was added toa cooled (−78° C.) solution of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethyl-sulfonyl)anilino]pyrazol-1-yl]-4-[2-[methoxy(methyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate(600 mg, 1.0 mmol) in tetrahydrofuran (10 mL). The mixture was allowedto stir for 30 mins at −78° C. then quenched with 5% aqueous citric acid(50 mL) and saturated sodium sulfate (50 mL). iPrOAc (100 mL) was addedand the precipitated solid was removed by filtration through Celite. Thelayers of the filtrate were separated, the organic extract was washedwith brine; the aqueous layer was extracted with dichloromethane (100mL). The combined organic layer was dried over sodium sulfate, filtered,and concentrated under reduced pressure to afford 620 mg of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]pyrazol-1-yl]-4-(2-oxoethyl)piperidine-1-carboxylateas a white solid which was used without further purification.

To a solution of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)-anilino]pyrazol-1-yl]-4-(2-oxoethyl)piperidine-1-carboxylate(270 mg, 0.50 mmol) in acetonitrile (3 mL) was added 1,2-ethanedithiol(0.41 mL, 470 mg, 5.0 mmol) followed by p-toluenesulfonic acidmonohydrate (10 mg, 0.05 mmol). The mixture was stirred at roomtemperature for 16 h then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha gradient of 0 to 5% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 220 mg (71%) of tert-butyl 4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]-pyrazol-1-yl]-4-(1,3-dithiolan-2-ylmethyl)piperidine-1-carboxylateas a white solid.

To a solution of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]-pyrazol-1-yl]-4-(1,3-dithiolan-2-ylmethyl)piperidine-1-carboxylate(220 mg, 0.36 mmol) in tetrahydrofuran (4 mL) was added a slurry ofRaney nickel (Raney 2800, approx. 50% (w/v) in water, 1 mL). The mixturewas stirred under a blloon of hydrogen at RT for 1 h.

The solid was removed by filtration through Celite and the filtrateconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel eluting with a gradient of 0 to 5% methanolin dichloromethane. The appropriate fractions were combined andconcentrated under reduced pressure to afford 73 mg (39%) of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]pyrazol-1-yl]-4-ethyl-piperidine-1-carboxylateas a white solid.

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl4-[4-carbamoyl-3-[4-(difluoromethylsulfonyl)anilino]pyrazol-1-yl]-4-ethyl-piperidine-1-carboxylate(73 mg, 0.14 mmol) in dichloromethane (3 mL) and the mixture was stirred1 h at room temperature. Toluene (5 mL) was added, and the mixture wasconcentrated under reduced pressure. The residue was co-evaporated twomore times with toluene (2×5 mL) to afford3-[4-(difluoromethylsulfonyl)anilino]-1-(4-ethyl-4-piperidyl)pyrazole-4-carboxamidetrifluoroacetate salt, the entirety of which was used in the next stepwithout purification.

A mixture of3-[4-(difluoromethylsulfonyl)anilino]-1-(4-ethyl-4-piperidyl)-pyrazole-4-carboxamidetrifluoroacetate salt (all of the crude material from the previousstep), 3-hydroxy-6-fluorobenzaldehyde (29 mg, 0.21 mmol, 1.5 equiv) andsodium triacetoxyborohydride (59 mg, 0.28 mmol, 2.0 equiv) inacetonitrile (2 mL) was stirred for 16 h at room temperature. Incompleteconversion was noted, methanol (1 mL), 3-hydroxy-6-fluorobenzaldehyde(29 mg, 0.21 mmol), and sodium triacetoxyborohydride (59 mg, 0.28 mmol)were added and stirring continued for 2 h at room temperature. Thereaction mixture was directly loaded for purification by flashchromatography on silica gel eluting with a gradient of 0 to 20%methanol in dichloromethane. The appropriate fractions were combined andconcentrated under reduced pressure to afford 36 mg (47%) of3-[4-(difluoromethylsulfonyl)anilino]-1-[4-ethyl-1-[(2-fluoro-5-hydroxy-phenyl)methyl]-4-piperidyl]pyrazole-4-carboxamideas a white solid. LC/MS (Method J, ESI): [M+H]⁺=552.1, R_(T)=3.58 min;¹H NMR (400 MHz, DMSO-d₆): δ (ppm) 11.94 (s, 2H), 9.76 (s, 1H), 9.26 (s,1H), 8.45 (s, 1H), 7.86-7.75 (m, 4H), 7.62 (s, 1H), 7.40-6.57 (m, 4H),3.44-3.32 (m, 2H), 2.68-2.61 (m, 2H), 2.41-2.33 (m, 2H), 2.14-2.09 (m,3H), 1.91 (s, 2H), 1.81-1.72 (m, 2H), 0.54 (t, J=7.1 Hz, 4H).

Example 302 (General Procedure X)

1-((1S,4S)-1-ethyl-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide&1-((1R,4R)-1-ethyl-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-3-((4-(methylsulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide

To a cooled (0° C.) solution of potassium tert-butoxide (4.6 g, 41 mmol)in tetrahydrofuran (50 mL) was added2-diethoxyphosphoryl-N-methoxy-N-methyl-acetamide (10 g, 43 mmol). Themixture was allowed to warm to room temperature over 30 mins and stirredfor an additional 1 h. The mixture was cooled to −78° C., and a solutionof 4-benzyloxycyclohexanone (7.9 g, 39 mmol, 1.0 equiv) tetrahydrofuran(50 mL) was added. The mixture was allowed to slowly warm to roomtemperature and was stirred for 16 h. The mixture was diluted with water(250 mL) and extracted with isopropyl acetate (3×100 mL). The combinedorganic layer was washed with water and brine, dried over sodium sulfateand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel eluting with a gradient of 0 to 70%isopropyl acetate in heptane. The appropriate fractions were combinedand concentrated under reduced pressure to afford 10 g (89%) of2-(4-benzyloxycyclohexylidene)-N-methoxy-N-methyl-acetamide as acolorless oil.

To a solution of 3-amino-1H-pyrazole-4-carboxamide (5 g, 39.6 mmol) and2-(4-benzyloxycyclohexylidene)-N-methoxy-N-methyl-acetamide (10.0 g,34.6 mmol) in N,N-dimethylformamide (50 mL) was added cesium carbonate(12.4 g, 38.0 mmol). The mixture was stirred for 16 h at roomtemperature. Low conversion was noted, so to the mixture was added1,8-diazabicyclo[5.4.0]undec-7-ene (5.2 mL, 34.6 mmol) and the mixturewas heated to 60° C. for 3 h. After this time the reaction was quenchedwith 5% aq. Citric acid (150 mL) and extracted with isopropyl acetate(3×100 mL). The combined organic layer was washed with water and brine,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha gradient of 0 to 8% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 3.3 g (23%) of3-amino-1-[4-benzyloxy-1-[2-[methoxy(methyl)amino]-2-oxo-ethyl]cyclohexyl]pyrazole-4-carboxamideas a white solid.

A degassed solution of3-amino-1-[4-benzyloxy-1-[2-[methoxy(methyl)amino]-2-oxo-ethyl]cyclohexyl]pyrazole-4-carboxamide(1.0 g, 2.4 mmol), 1-bromo-4-methylsulfonyl-benzene (622 mg, 2.65 mmol),potassium phosphate tribasic (1.05 g, 4.8 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (53 mg, 0.12mmol) and tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) in1,4-dioxane (20 mL) and tert-butyl alcohol (5 mL) was heated for 16 h at80° C. The mixture was allowed to cool to room temperature and the solidremoved by filtration through Celite and the filtrate concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel eluting with a gradient of 0 to 7% methanol indichloromethane. The appropriate fractions were combined andconcentrated under reduced pressure to afford 1.36 g (99%) of1-[4-benzyloxy-1-[2-[methoxy(methyl)amino]-2-oxo-ethyl]cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a white solid.

Diisobutylaluminum hydride (1M in heptane, 24 mL, 24 mmol) was added toa cooled (−78° C.) solution of of1-[4-benzyloxy-1-[2-[methoxy(methyl)amino]-2-oxo-ethyl]cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamide(1.36 g, 2.4 mmol) in tetrahydrofuran (20 mL). The mixture was stirred30 mins at −78° C. then quenched with saturated sodium sulfate (25 mL)and stirred 10 mins. Solid anhydrous sodium sulfate was added and themixture stirred for an additional 30 mins. The solid was removed byfiltration through Celite and the pad was washed thoroughly withtetrahydrofuran. The filtrate was concentrated under reduced pressureand purified by flash chromatography on silica gel eluting with agradient of 0 to 10% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 800 mg (66%) of1-[4-benzyloxy-1-(2-oxoethyl)cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a white solid.

To a solution of1-[4-benzyloxy-1-(2-oxoethyl)cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamide(800 mg, 1.6 mmol) in tetrahydrofuran (10 mL) was added1,2-ethanedithiol (1.29 mL, 15.7 mmol) and p-toluenesulfonic acidmonohydrate (30 mg, 0.16 mmol). The mixture was stirred at roomtemperature for 16 h then concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha gradient of 0 to 5% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 530 mg (58%) of1-[4-benzyloxy-1-(1,3-dithiolan-2-ylmethyl)cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a white solid.

A mixture of1-[4-benzyloxy-1-(1,3-dithiolan-2-ylmethyl)cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamide(530 mg, 0.9 mmol) and a slurry of Raney nickel (Raney 2800, approx. 50%(w/v) in water, 2 mL) in tetrahydrofuran (4 mL) was stirred at roomtemperature for 16 h under a balloon of hydrogen. The solid was removedby filtration through Celite and the filtrate concentrated under reducedpressure. The residue was purified by flash chromatography on silica geleluting with a gradient of 0 to 5% methanol in dichloromethane. Theappropriate fractions were combined and concentrated under reducedpressure to afford 100 mg (22%) of1-(4-benzyloxy-1-ethyl-cyclohexyl)-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a white solid.

To a solution of1-(4-benzyloxy-1-ethyl-cyclohexyl)-3-(4-methylsulfonylanilino)pyrazole-4-carboxamide(100 mg, 0.20 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) wasadded 10% palladium on carbon (43 mg, 0.04 mmol). The mixture wasstirred for 16 h at room temperature under a balloon of hydrogen. Lowconversion was noted, so to the mixture was added 10% palladiumhydroxide (57 mg, 0.04 mmol) and the mixture stirred for 72 h at 50° C.under a balloon of hydrogen. The solid was removed by filtration throughCelite and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel eluting with a gradient of 0 to10% methanol in dichloromethane. The appropriate fractions were combinedand concentrated under reduced pressure to afford 10 mg (12%) of1-(1-ethyl-4-hydroxy-cyclohexyl)-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a white solid.

Dess-Martin periodinane (21 mg, 0.05 mmol) was added to a solution of1-(1-ethyl-4-hydroxy-cyclohexyl)-3-(4-methylsulfonylanilino)pyrazole-4-carboxamide(10 mg, 0.02 mmol) in dichloromethane (2 mL) and the mixture was stirred1 h at room temperature. Incomplete conversion was noted, so to themixture was added more Dess-Martin periodinane (21 mg, 0.05 mmol) andstirring continued for 1 h at room temperature. A further portion wasadded of Dess-Martin periodinane (21 mg, 0.05 mmol) was added and themixture stirred at room temperature for 1 h. Acetonitrile (2 mL),3-(trifluoromethyl)azetidine hydrochloride (32 mg, 0.20 mmol), andsodium triacetoxyborohydride (42 mg, 0.20 mmol,) were added and themixture was stirred 1 h at room temperature. The reaction mixture wasloaded directly on to the column for purification by flashchromatography on silica gel eluting with a gradient of 0 to 25%methanol in dichloromethane. The appropriate fractions were combined andconcentrated under reduced pressure to afford 15 mg of1-[1-ethyl-4-[3-(trifluoromethyl)azetidin-1-yl]cyclohexyl]-3-(4-methylsulfonylanilino)pyrazole-4-carboxamideas a mixture of diastereomers. The diastereomers were resolved usingchiral SFC with the following conditions: Column: Chiralpak IA 150×21.2mm I.D., 5 m Mobile phase: A: CO₂ B: Methanol (0.1% NH₄OH) Isocratic:25% B in 6 min Flow rate: 70 mL/min Column temperature: 40° C., BPR: 100bar, Detector, UV 254 nm to give two fractions. Relative configurationwas arbitrarily assigned to each diastereomer:

First eluted fraction, 2.1 mg (17%) as a white solid, LC/MS (Method J,ESI): [M+H]⁺=514.2, R_(T)=3.21 min

Second eluted fraction, 1.9 mg (15%) as a white solid, LC/MS (Method J,ESI): [M+H]⁺=514.2, R_(T)=3.00 min

Example 303 (General Procedure Y)

Diethyl(4-((4-carbamoyl-1-((1R,4R)-1-(cyanomethyl)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1H-pyrazol-3-yl)amino)phenyl)phosphonate

A degassed suspension of 1-bromo-4-iodo-benzene (2.42 g, 8.54 mmol),cesium carbonate (3.8 g, 11.6 mmol),tetrakis(triphenylphosphine)palladium(O) (449 mg, 0.38 mmol) and diethylphosphite (1 mL, 1.1 g, 7.82 mmol) in tetrahydrofuran (10 mL) was heatedunder microwave irradiation at 120° C. for 30 mins. The mixture wasallowed to cool to room temperature, the solid removed by filtrationthrough Celite and the filtrate concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha gradient of 0 to 5% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 430 mg (19%) of 1-bromo-4-diethoxyphosphoryl-benzene as a paleyellow oil.

A degassed mixture of3-amino-1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-1H-pyrazole-4-carboxamide(400 mg, 1.3 mmol), 1-bromo-4-dimethylphosphoryl-benzene (430 mg, 1.5mmol), potassium phosphate tribasic (573 mg, 2.6 mmol),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (29 mg, 0.065mmol) and tris(dibenzylideneacetone)dipalladium(0) (15 mg, 0.016 mmol)in 1,4-dioxane (8 mL) was heated for 16 h at 100° C. The mixture wasallowed to cool to room temperature, the solid removed by filtrationthrough Celite and the filtrate concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel eluting witha gradient of 0 to 10% methanol in isopropyl acetate. The appropriatefractions were combined and concentrated under reduced pressure toafford 160 mg (24%) of1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-3-(4-diethoxyphosphorylanilino)pyrazole-4-carboxamideas a white solid.

Formic acid (4 mL) was added to a suspension of1-[8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl]-3-(4-dimethylphosphorylanilino)pyrazole-4-carboxamide(160 mg, 0.31 mmol) in water (0.2 mL) and the mixture was stirred atroom temperature for 16 h. The mixture was concentrated under reducedpressure to afford 146 mg (100%) of1-[1-(cyanomethyl)-4-oxo-cyclohexyl]-3-(4-diethoxyphosphorylanilino)pyrazole-4-carboxamideas a white solid which was used without further purification.

To a mixture of 3-(trifluoromethyl)azetidine hydrochloride (75 mg, 0.46mmol),1-[1-(cyanomethyl)-4-oxo-cyclohexyl]-3-(4-dimethylphosphorylanilino)pyrazole-4-carboxamide(146 mg, 0.31 mmol) in acetonitrile (2 mL) was added sodiumtriacetoxyborohydride (131 mg, 0.62 mmol) and the mixture was stirredfor 2 h at room temperature. The mixture was loaded directly forpurification by flash chromatography on silica gel eluting with agradient of 0 to 20% methanol in dichloromethane. The appropriatefractions were combined and concentrated under reduced pressure toafford 50 mg (28%) of diethyl(4-((4-carbamoyl-1-((1R,4R)-1-(cyanomethyl)-4-(3-(trifluoromethyl)azetidin-1-yl)cyclohexyl)-1H-pyrazol-3-yl)amino)phenyl)phosphonateas a white solid. LC/MS (Method J, ESI): [M+H]⁺=583.3, R_(T)=3.20 min;¹H NMR (400 MHz, DMSO-d₆) (ppm) δ 9.42 (s, 1H), 8.50 (s, 1H), 7.70-7.62(m, 3H), 7.62-7.52 (m, 2H), 7.22 (s, 1H), 4.05-3.89 (m, 4H), 3.47-3.18(m, 3H), 3.15-3.07 (m, 4H), 2.28-2.19 (m, 1H), 2.16-2.08 (m, 4H),1.50-1.36 (m, 4H), 1.22 (t, J=7.0 Hz, 6H).

Example 304 (General Procedure W)

1-(1-(2-Cyanoacetyl)-4-ethylpiperidin-4-yl)-3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamide

To a solution of1-[4-(cyanomethyl)-4-piperidyl]-3-(cyclopropane-carbonyl-amino)pyrazole-4-carboxamide(88 mg, 0.16 mmol) in N,N-dimethylformamide (2 mL) was addedsequentially cyanoacetic acid (17 mg, 0.19 mmol),N,N-diisopropylethylamine (0.11 mL, 84 mg, 0.65 mmol),1-hydroxybenzotriazole (27 mg, 0.19 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (40 mg, 0.21mmol). The mixture was stirred for 16 h at room temperature. Thereaction mixture was loaded directly for purification by reverse phaseHPLC (Conditions: Column, Gemini-NX C18 5 um, 50×30 mm; mobile phase:Water (0.1% formic acid) and CH₃CN (20% CH₃CN up to 60% in 10 min); Flowrate 60 ml/min). Appropriate fractions were combined and evaporated toafford 30 mg (36%) of1-(1-(2-cyanoacetyl)-4-ethylpiperidin-4-yl)-3-((4-((difluoromethyl)sulfonyl)phenyl)amino)-1H-pyrazole-4-carboxamideas a white solid. LC/MS (Method J, ESI): [M+H]⁺=495.1, R_(T)=4.50 min;¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 9.74 (s, 1H), 8.48 (s, 1H), 7.88-7.74(m, 4H), 7.61 (s, 1H), 7.36-6.97 (m, 2H), 4.16-3.96 (m, 3H), 3.65-3.52(m, 1H), 3.17-3.04 (m, 1H), 3.00-2.87 (m, 1H), 2.45-2.30 (m, 2H),2.03-1.90 (m, 1H), 1.90-1.70 (m, 3H), 0.57 (t, J=7.4 Hz, 3H).

Description of LCMS Methods Referenced Above Method A

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 μm particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 2.20 1.0 0 100 3.201.0 0 100 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD Method B

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.0 95 5 3.20 1.0 40 60 3.801.0 0 100 4.70 1.0 0 100 4.80 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD Method C

Experiments were performed on a SHIMADZU LCMS-2020 with a Shim-packXR-ODS column (50×3 mm Shim-pack XR-ODS, 2.2 m particle size), elutionwith solvent A: water+0.05% TFA; solvent B: acetonitrile+0.05% TFA.

Gradient:

Gradient - Time flow ml/min % A % B 0.01 1.0 95 5 2.20 1.0 5 95 3.20 1.05 95 3.30 1.0 95 5

Detection—UV (220 and 254 nm) and ELSD Method D

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Gemini-NX C18 110A, 3.0 m particlesize), elution with solvent A: water 5 mM NH₄HCO₃; solvent B:acetonitrile.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 90 10 3.20 1.2 40 60 4.001.2 5 95 4.40 1.2 5 95 4.50 1.2 90 10

Detection—UV (220 and 254 nm) and ELSD Method E

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Gemini-NX C18 110A, 3.0 m particlesize), elution with solvent A: water 5 mM NH₄HCO₃; solvent B:acetonitrile.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 90 10 2.00 1.2 5 95 3.201.2 5 95 3.30 1.2 90 10

Detection—UV (220 and 254 nm) and ELSD Method F

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Gemini-NX C18 110A, 3.0 m particlesize), elution with solvent A: water 5 mM NH₄HCO₃; solvent B:acetonitrile.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 90 10 2.00 1.2 5 95 2.701.2 5 95 2.80 1.2 90 10

Detection—UV (220 and 254 nm) and ELSD Method G

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×2.1 mm Ascentis Express C18, 2.7 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.01 1.0 95 5 2.00 1.0 5 95 2.70 1.05 95

Detection—UV (220 and 254 nm) and ELSD Method H

Experiments were performed on a SHIMADZU LCMS-2020 with an AscentisExpress C18 column (50×2.1 mm, 2.7 m particle size), elution withsolvent A: water+0.05% TFA; solvent B: acetonitrile+0.05% TFA.

Gradient:

Gradient - Time flow ml/min % A % B 0.01 1.0 95 5 4.20 1.0 30 70 4.501.0 5 95 5.00 1.0 5 95

Detection—UV (220 and 254 nm) and ELSD Method I

Experiments were performed on a SHIMADZU LCMS-2020 with an AscentisExpress C18 column (50×2.1 mm, 2.7 m particle size), elution withsolvent A: water+0.05% TFA; solvent B: acetonitrile+0.05% TFA.

Gradient:

Gradient - Time flow ml/min % A % B 0.01 1.0 95 5 2.00 1.0 0 100 2.701.0 0 100

Detection—UV (220 and 254 nm) and ELSD Method J

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 3.50 1.2 30 70 3.701.2 0 100 4.70 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method K (LCMS 15)

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 2.00 1.2 5 95 2.70 1.25 95 2.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method L (LCMS34)

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Gemini-NX C18 110A, 3.0 m particlesize), elution with solvent A: water 5mNH₄HCO₃; solvent B: acetonitrile.Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 80 20 3.50 1.2 40 60 4.001.2 5 95 4.70 1.2 5 95 4.80 1.2 90 10

Detection—UV (220 and 254 nm) and ELSD Method M (LCMS53)

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 3.50 1.2 40 60 3.701.2 0 100 4.70 1.2 0 100 4.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method N (LCMS53)

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (50×3 mm Shim-pack XR-ODS, 2.2 m particlesize), elution with solvent A: water+0.05% trifluoroacetic acid; solventB: acetonitrile+0.05% trifluoroacetic acid.

Gradient:

Gradient - Time flow ml/min % A % B 0.00 1.2 95 5 1.10 1.2 0 100 1.701.2 0 100 1.75 1.2 95 5

Detection—UV (220 and 254 nm) and ELSD Method O

Experiments performed on an Agilent 1290 UHPLC coupled with Agilent MSD(6140) mass spectrometer using ESI as ionization source. The LCseparation was using a Phenomenex XB-C18, 1.7 μm, 50×2.1 mm column witha 0.4 ml/minute flow rate. Solvent A is water with 0.1% formic acid andsolvent B is acetonitrile with 0.1% formic acid. The gradient consistedwith 2-98% solvent B over 7 min and hold 98% B for 1.5 min followingequilibration for 1.5 min. LC column temperature is 40° C. UV absorbancewas collected at 220 nm and 254 nm and mass spec full scan was appliedto all experiments.

Method P

Experiments were performed on a SHIMADZU LCMS-2020 with aC18-reverse-phase column (Waters BEH 30×2.1 mm, 1.7 μm particle size),elution with solvent A: water+0.1% formic acid; solvent B:acetonitrile+0.1% formic acid. Gradient:

Gradient - Time (min) flow ml/min % A % B 0 0.7 98 2 2 0.7 2 98 2.19 0.72 98 2.2 0.7 98 2 2.5 0.7 98 2

Detection—UV (254 nm)

The examples in the following table were prepared using similar methodsas described above. Absolute configuration was arbitrarily assigned toeach stereoisomer.

TABLE 2 LCMS Procedures. General Example Procedure Structure m/z 22 B

421 23 C

399 24 C

373 25 C

425 26 C

435 27 C

467 28 C

417 29 C

417 30 C

417 31 C

439 32 C

413 33 D

316 34 D

422 35 D

431 36 D

431 37 E

483 38 E

483 39 E

490 40 E

407 41 E

437 42 E

437 43 E

437 44 E

500 45 E

500 46 E

500 47 E

491 48 E

491 49 E

491 50 E

485 51 E

485 52 E

485 53 E

533 54 E

533 55 E

533 56 E

425 57 E

425 58 E

441 59 E

441 60 E

441 61 E

475 62 E

475 63 E

475 64 E

432 65 E

432 66 E

432 67 E

507 68 E

507 69 E

485 70 E

485 71 E

485 72 E

446 73 E

447 74 E

562 75 E

514 76 E

464 77 E

503 78 E

518 79 E

518 80 E

518 81 E

498 82 E

487 83 E

541 84 E

476 85 E

473 86 E

474 87 E

473 88 E

523 89 E

474 90 E

473 91 E

465 92 E

473 93 E

554 94 E

528 95 E

496 96 E

413 97 E

436 98 E

591 99 F

345 100 F

345 101 F

401 102 F

401 103 F

415 104 F

415 105 F

399 106 F

399 107 F

411 108 F

411 109 F

421 110 F

421 111 F

439 112 F

439 113 F

439 114 F

439 115 F

439 116 F

439 117 F

455 118 F

455 119 F

455 120 F

455 121 F

446 122 F

446 123 F

446 124 F

446 125 F

427 126 F

427 127 F

497 128 F

497 129 F

427 130 F

427 131 G

469 132 G

469 133 G

545 134 G

545 135 G

497 136 G

497 137 G

455 138 G

455 139 H

517 140 H

501 141 H

541 142 H

501 143 H

501 144 H

554 145 H

554 146 H

517 147 H

517 148 H

523 149 H

523 150 H

551 151 H

551 152 H

513 153 H

513 154 H

511 155 H

511 156 H

513 157 H

527 158 H

484 159 H

484 160 H

497 161 H

508 162 H

513 163 H

517 164 I

425 165 I

425 166 J

552 167 K

443 168 L

435 169 L

441 170 L

427 171 L

409 172 F

421 173 F

421 174 F

449 175 F

449 176 C

439 177 C

439 178 F

407 179 F

407 180 F

389 181 F

389 182 K

429 183 E

421 184 E

425 185 H

484 186 O

489 187 O

503 188 H

502 189 H

527 190 H

573 191 H

517 192 I

526 193 I

502 194 H

513 195 R

507 196 R

492 197 O

464 198 O

492 199 I

492 200 R

482 201 I

520 202 H

502 203 R

510 204 H

499 205 F

465 206 O

507 207 I

535 208 R

525 209 E

515 210 P

484 211 P

484 212 I

545 213 I

531 214 I

491 215 I

491 216 R

509 217 I

519 218 I

544 219 I

544 220 R

481 221 I

570 222 I

570 223 I

505 224 R

497 225 R

496 226 R

500 227 I

545 228 I

532 229 I

505 230 I

532 231 I

532 232 R

509 233 I

507 234 I

507 235 R

497 236 R

497 237 R

515 238 R

515 239 R

500 240 I

560 241 R

527 242 I

537 243 Q

455 244 R

497 245 A

483 246 R

495 247 R

511 248 R

543 249 R

512 250 I

556 251 R

510 252 R

526 253 E

488 254 I

525 255 I

492 256 R

529 257 R

495 258 R

511 259 I

465 260 I

449 261 I

491 262 Q

473 263 R

525 264 R

514 265 F

493 266 Q

463 267 R

496 268 R

481 269 R

497 270 R

439 271 I

507 272 R

500 273 R

465 274 R

489 275 A

473 276 A

473 277 E

490 278 R

482 279 A

431 280 I

483 281 R

455 282 A

407 283 R

483 284 R

457 285 R

475 286 I

508 287 R

498 288 A

474 289 R

473 290 A

441 291 S

543 292 R

463 293 R

449 294 S

501 295 S

545 296 R

545 297 R

457 298 T

453 299 U

471 300 S

491 301 V

552 302 X

514 303 Y

583 304 W

495

Using procedures similar to those described herein, the followingcompounds of Formula (I) can also be prepared, and stereoisomers andsalts thereof.

Enzymatic Assays

JAK Enzyme Assays were Carried Out as Follows:

The activity of the isolated recombinant JAK1 and JAK2 kinase domain wasmeasured by monitoring phosphorylation of a peptide derived from JAK3(Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr, fluorescently labeledon the N-terminus with 5-carboxyfluorescein) using the Caliper LabChip®technology (Caliper Life Sciences, Hopkinton, Mass.). To determineinhibition constants (K_(i)), compounds were diluted serially in DMSOand added to 50 μL kinase reactions containing purified enzyme (1.5 nMJAK1, or 0.2 nM JAK2), 100 mM HEPES buffer (pH 7.2), 0.015% Brij-35, 1.5μM peptide substrate, ATP (25 μM), 10 mM MgCl₂, 4 mM DTT at a final DMSOconcentration of 2%. Reactions were incubated at 22° C. in 384-wellpolypropylene microtiter plates for 30 minutes and then stopped byaddition of 25 μL of an EDTA containing solution (100 mM HEPES buffer(pH 7.2), 0.015% Brij-35, 150 mM EDTA), resulting in a final EDTAconcentration of 50 mM. After termination of the kinase reaction, theproportion of phosphorylated product was determined as a fraction oftotal peptide substrate using the Caliper LabChip® 3000 according to themanufacturer's specifications. K_(i) values were then determined usingthe Morrison tight binding model (Morrison, J. F., Biochim. Biophys.Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth.Enzymol., 63:437-467 (1979)) modified for ATP-competitive inhibition[K_(i)=K_(i,app)/(1+[ATP]/K_(m,app))].

JAK1 Pathway Assay in Cell Lines was Carried Out as Follows:

Inhibitor potency (EC₅₀) was determined in cell-based assays designed tomeasure JAK1 dependent STAT phosphorylation. As noted above, inhibitionof IL-4, IL-13, and IL-9 signalling by blocking the Jak/Stat signalingpathway can alleviate asthmatic symptoms in pre-clinical lunginflammation models (Mathew et al., 2001, J Exp Med 193(9): 1087-1096;Kudlacz et. al., 2008, Eur J. Pharmacol 582(1-3): 154-161).

In one assay approach, TF-1 human erythroleukemia cells obtained fromthe American Type Culture Collection (ATCC; Manassas, Va.) were used tomeasure JAK1-dependent STAT6 phosphorylation downstream of IL-13stimulation. Prior to use in the assays, TF-1 cells were starved ofGM-CSF overnight in OptiMEM medium (Life Technologies, Grand Island,N.Y.) supplemented with 0.5% charcoal/dextran stripped fetal bovineserum (FBS), 0.1 mM non-essential amino acids (NEAA), and 1 mM sodiumpyruvate. The assays were run in 384-well plates in serum-free OptiMEMmedium using 300,000 cells per well. In a second assay approach, BEAS-2Bhuman bronchial epithelial cells obtained from ATCC were plated at100,000 cells per well of a 96-well plate one day prior to theexperiment. The BEAS-2B assay was run in complete growth medium(bronchial epithelial basal medium plus bulletkit; Lonza; Basel,Switzerland).

Test compounds were serially diluted 1:2 in DMSO and then diluted 1:50in medium just before use. Diluted compounds were added to the cells,for a final DMSO concentration of 0.2%, and incubated for 30 min (forthe TF-1 assay) or 1 hr (for the BEAS-2B assay) at 37° C. Then, cellswere stimulated with human recombinant cytokine at their respective EC₉₀concentrations, as previously determined for each individual lot. Cellswere stimulated with IL-13 (R&D Systems, Minneapolis, Minn.) for 15 minat 37° C. The TF-1 cell reactions were stopped by the direct addition of10× lysis buffer (Cell Signaling Technologies, Danvers, Mass.), whereasthe BEAS-2B cell incubations were halted by the removal of medium andaddition of 1× lysis buffer. The resultant samples were frozen in theplates at −80° C. Compound mediated inhibition of STAT6 phosphorylationwas measured in the cell lysates using MesoScale Discovery (MSD)technology (Gaithersburg, Md.). EC₅₀ values were determined as theconcentration of compound required for 50% inhibition of STATphosphorylation relative to that measured for the DMSO control.

Table 3 provides JAK1 K_(i), JAK2 K_(i) and IL-13-pSTAT6 IC₅₀information for the noted Examples.

TABLE 3 IL-13 p-STAT6 BEAS-2B Example JAK1 K_(i) (uM) JAK2 K_(i) (uM)IC₅₀ (uM) 1 >0.5621 0.2525 >1 2 0.0012 0.0061 0.373 3 0.0064 0.0157 40.0082 0.0345 5 0.0228 0.1892 6 0.0008 0.0036 0.031 7 >0.5621 >0.3188 80.0017 0.0110 0.194 9 0.0022 0.0243 0.436 10 >0.5621 >0.3188 >1 110.0004 0.0010 0.383 12 0.0013 0.0068 0.103 13 0.0006 0.0022 0.037 140.0002 0.0004 0.016 15 0.0042 0.0307 0.282 16 0.0005 0.0024 0.085 170.0040 0.0694 0.948 18 0.0308 0.2351 19 0.0693 >0.3188 20 0.4473 >0.318821 0.0023 0.0484 >1 22 0.0374 0.1511 23 0.0045 0.0194 0.250 24 0.03560.0767 25 0.0812 >0.3188 26 0.0115 0.2027 27 0.1024 0.7813 28 0.01210.0309 29 0.0101 0.0119 30 0.0086 0.0532 31 0.0964 0.1892 32 0.07180.1964 33 0.0156 0.0765 34 0.0248 0.2760 35 0.0202 0.274936 >0.5621 >0.3188 37 0.0346 0.2680 38 0.0081 0.1068 39 0.0982 >0.318840 0.0079 0.0967 41 0.0538 >0.3188 42 0.0078 0.0949 43 0.0258 0.1695 440.0276 0.1736 45 0.0019 0.0085 >1 46 0.0414 0.2841 47 0.0341 0.2497 480.0277 0.1887 49 0.0233 0.1903 50 0.0062 0.0664 51 0.0065 0.0537 520.0023 0.0209 0.102 53 0.0071 0.1006 54 0.0107 0.1016 55 0.0032 0.03140.098 56 0.0024 0.0243 0.363 57 0.0039 0.0490 0.128 58 0.0044 0.04260.287 59 0.0047 0.0359 60 0.0039 0.0234 0.094 61 0.0083 0.1176 62 0.02760.2848 63 0.0144 0.1335 64 0.0073 0.0835 >1 65 0.0137 0.1228 66 0.00400.0502 0.910 67 0.1002 >0.3188 68 0.0390 >0.3188 69 0.0152 0.1236 700.0310 >0.3188 71 0.0341 >0.3188 72 0.0083 0.0313 73 0.0573 0.2722 740.0061 0.0587 75 0.0027 0.0140 >1 76 0.0039 0.0369 >1 77 0.0026 0.04470.227 78 0.0029 0.0049 >1 79 0.0030 0.0142 >1 80 0.0012 0.0036 >1 810.0044 0.0384 >1 82 0.0049 0.0143 0.688 83 0.0161 0.3128 840.0850 >0.3188 85 0.0451 0.1698 86 0.0997 >0.3188 87 0.0022 0.0251 0.35088 0.0263 0.1502 89 0.0007 0.0068 0.119 90 0.0072 0.1334 91 0.00830.1730 92 0.0109 0.0881 93 0.0721 >0.3188 94 0.0041 0.0218 >1 95 0.00120.0063 0.275 96 0.0241 0.1133 97 0.0410 0.1630 98 0.0746 0.1519 990.0922 >0.3188 100 >0.5621 >0.3188 101 >0.5621 >0.3188 102 0.0033 0.03180.933 103 0.0380 >0.3188 104 >0.5621 >0.3188 105 >0.5621 >0.3188 1060.0233 0.3328 107 0.0033 0.0431 >1 108 0.4659 0.2048 109 >0.5621 >0.3188110 0.0053 0.2542 111 0.0095 0.0873 112 >0.5621 >0.3188 113 0.01440.1871 114 >0.5621 >0.3188 115 0.0219 0.2998 116 0.1639 >0.3188 1170.0037 0.0547 0.611 118 >0.5621 >0.3188 119 0.4368 >0.3188 120 0.01200.1146 121 0.0146 0.2819 122 0.5621 >0.3188 123 >0.5621 >0.3188 1240.0327 0.2725 125 0.0073 0.0783 126 0.1879 >0.3188 127 >0.5621 >0.3188128 0.0046 0.0464 0.349 129 0.0033 0.0163 0.393 130 >0.5621 >0.3188 1310.0028 0.0187 0.334 132 0.2170 >0.3188 133 0.0025 0.0156 0.162134 >0.5621 >0.3188 135 0.0024 0.0243 0.170 136 0.4629 >0.3188 1370.0027 0.0217 >1 138 >0.5621 >0.3188 139 0.0004 0.0010 0.104 140 0.00060.0044 0.049 141 0.0008 0.0034 0.062 142 0.0017 0.0129 0.060 143 0.00070.0055 0.049 144 0.0088 0.0635 145 0.0031 0.0155 >1 146 0.0011 0.00820.095 147 0.0021 0.0320 0.051 148 0.0018 0.0212 0.048 149 0.0007 0.00470.041 150 0.0159 0.2075 151 0.0034 0.1543 0.286 152 0.0013 0.0078 0.126153 0.0011 0.0308 0.103 154 0.0015 0.0087 0.116 155 0.0006 0.0073 0.060156 0.0006 0.0043 0.209 157 0.0016 0.0137 0.104 158 0.0080 0.0394 1590.0190 0.1012 160 0.0032 0.0120 0.186 161 0.0055 0.0353 1.014 162 0.00310.0106 0.293 163 0.0021 0.0185 0.103 164 0.0027 0.0090 0.275 165 0.02710.2112 166 0.0022 0.0800 0.068 167 0.0023 0.0287 0.833 168 0.0075 0.0933169 0.0037 0.0483 >1 170 0.0067 0.0709 171 0.0066 0.0303172 >0.5621 >0.3188 173 0.0087 0.0713 174 >0.5621 >0.3188 175 0.01410.3210 176 0.3022 >0.3188 177 0.0187 0.2255 178 0.0047 0.0184 0.167179 >0.5621 >0.3188 180 0.0055 0.0173 0.168 181 >0.5621 >0.3188 1820.0047 0.0507 0.675 183 0.0883 >0.3188 184 0.0904 0.1595 0.177 1850.0023 0.209 186 0.00024 0.001 0.068 187 0.00052 0.0031 0.074 188 0.00060.0014 0.034 189 0.00033 0.0013 0.038 190 0.0011 0.011 0.093 191 0.00020.00032 0.082 192 0.00035 0.0012 0.028 193 0.00033 0.00026 0.048 1940.00063 0.0022 0.05 195 0.00011 0.00015 0.015 196 0.00026 0.00027 0.03197 0.0012 0.022 0.065 198 0.0012 0.0038 0.074 199 0.00052 0.00055 0.064200 0.00051 0.00096 0.039 201 0.00024 0.00023 0.023 202 0.00055 0.000740.074 203 0.00025 0.00022 0.015 204 0.001 0.0018 0.05 205 0.00089 0.00590.082 206 0.00018 0.0003 0.033 207 0.00011 0.00013 0.029 208 0.000170.00021 0.028 209 0.00049 0.0038 0.098 210 0.0021 0.0051 0.075 2110.00074 0.0046 0.026 212 0.00022 0.0003 0.027 213 0.00037 0.00028 0.022214 0.00031 0.00062 0.042 215 0.00024 0.00025 0.012 216 0.00074 0.00070.04 217 0.00066 0.00049 0.056 218 0.00035 0.00059 0.028 219 0.00170.0036 0.068 220 0.00027 0.00044 0.015 221 0.0003 0.0017 0.09 2220.00018 0.00043 0.052 223 0.00038 0.00034 0.012 224 0.00016 0.000150.019 225 0.00062 0.0013 0.044 226 0.00037 0.00056 0.049 227 0.000310.00063 0.054 228 0.0015 0.0077 0.077 229 0.00048 0.00077 0.025 2300.00051 0.0018 0.06 231 0.00036 0.0083 0.019 232 0.00032 0.00089 0.02233 0.0003 0.00045 0.039 234 0.00027 0.001 0.031 235 0.00032 0.000670.026 236 0.00021 0.0014 0.019 237 0.00022 0.0003 0.027 238 0.000290.00035 0.018 239 0.00051 0.00089 0.067 240 0.00019 0.00029 0.071 2410.00054 0.00051 0.029 242 0.0006 0.00051 0.055 243 0.0027 0.014 0.1 2440.0002 0.00037 0.067 245 0.00023 0.00092 0.014 246 0.00035 0.00052 0.019247 0.00035 0.00043 0.026 248 0.00028 0.00025 0.03 249 0.00052 0.000560.026 250 0.00031 0.00084 0.08 251 0.00034 0.0003 0.03 252 0.00030.00052 0.022 253 0.001 0.0056 0.056 254 0.00043 0.00082 0.043 2550.0012 0.00096 0.07 256 0.00015 0.00089 0.047 257 0.00073 0.0013 0.052258 0.00034 0.00029 0.034 259 0.00084 0.0018 0.05 260 0.00025 0.000350.032 261 0.00056 0.00082 0.021 262 0.0012 0.0037 0.057 263 0.00030.00024 0.025 264 0.00079 0.0014 0.088 265 0.0011 0.0042 0.088 2660.00077 0.005 0.057 267 0.00086 0.00084 0.051 268 0.0009 0.0019 0.043269 0.0006 0.00055 0.035 270 0.00041 0.0009 0.021 271 0.0026 0.015 0.083272 0.00068 0.0016 0.067 273 0.00033 0.00031 0.075 274 0.00058 0.000610.038 275 0.0011 0.0081 0.052 276 0.00025 0.0022 0.009 277 0.000740.0019 0.04 278 0.0011 0.0013 0.045 279 0.0012 0.014 0.092 280 0.00030.0004 0.016 281 0.0011 0.0022 0.036 282 0.00062 0.0096 0.048 283 0.00140.0029 0.077 284 0.0003 0.0005 0.048 285 0.00019 0.00023 0.022 2860.00043 0.0004 0.052 287 0.00035 0.00043 0.032 288 0.00028 0.0044 0.041289 0.00026 0.00055 0.015 290 0.0011 0.013 0.082 291 0.00086 0.00210.054 292 0.00055 0.0007 0.049 293 0.0003 0.00034 0.055 294 0.000740.0011 0.047 295 0.002 0.0029 0.085 296 0.00056 0.00059 0.052 2970.00053 0.00076 0.062 298 0.0006 0.00058 0.029 299 0.0011 0.003 0.085300 0.0015 0.0013 0.043 301 0.0015 0.002 0.1 302 0.00094 0.002 0.043 3030.00039 0.00066 0.034 304 0.00049 0.0028 0.220

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R^(1a)taken together with the atom to which they are attached form a 3-10membered carbocycle optionally substituted with R^(a) and optionallysubstituted with R^(b); or R¹ and R^(1a) taken together with the atom towhich they are attached form a 3-15 membered heterocycle optionallysubstituted with R and optionally substituted with R^(d); R² is—NR^(e)R^(f); R³ is —CH₃ or —CN; R^(a) is —NR^(r)R^(s) or —OR^(r); eachR^(b) is independently selected from the group consisting of halo,cyano, hydroxy, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, —NH₂, —NHCH₃, —N(CH₃)₂,—SH, and —SCH₃, wherein any C₁-C₆alkyl, and C₁-C₆alkoxy is optionallysubstituted with halo, cyano, hydroxy, oxo, C₁₋₃alkyl, C₁₋₃alkoxy, —NH₂,—NHCH₃, —N(CH₃)₂, —SH, or —SCH₃, wherein any C₁₋₃alkyl and C₁₋₃alkoxy isoptionally substituted with halo, hydroxy, cyano or oxo; R^(c) is—OR^(m), —SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), —NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 3-10membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or5-10 membered heteroaryl, wherein any C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl of R^(c) is optionally substituted with R^(x); each R^(d)is independently selected from the group consisting of halo, cyano,C₁-C₆alkyl, and C₁-C₆alkoxy, wherein any C₁-C₆alkyl, and C₁-C₆alkoxy isoptionally substituted with halo, hydroxy, cyano or oxo; R^(e) is H orC₁-C₄alkyl; R^(f) is —C(═O)—R^(g), or aryl that is optionallysubstituted with one or more groups selected from the group consistingof halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, —S(O)₂R^(h),and —P(═O)(OR^(k))₂; R^(g) is H, hydroxy, C₁-C₆alkyl, C₁-C₆alkoxy,—NR^(t)R^(u), or a 3-10 membered carbocyclyl that is optionallysubstituted with halo, hydroxy, cyano, oxo, C₁-C₃alkyl, C₂-C₃alkynyl,6-10 membered aryl, 5-6 membered heteroaryl, or 3-5 memberedcarbocyclyl, wherein any C₁-C₃alkyl, 6-10 membered aryl, 5-6 memberedheteroaryl, or 3-5 membered carbocyclyl is optionally substituted withhalo, hydroxy, cyano, or C₁-C₃alkyl; each R^(h) is independentlyselected from the group consisting of C₁-C₆alkyl that is optionallysubstituted with halo; each R^(k) is independently selected from thegroup consisting of H and C₁-C₆alkyl that is optionally substituted withhalo; R^(m) and R^(n) are independently selected from the groupconsisting of hydrogen, 3-6 membered heterocyclyl, 3-6 memberedcarbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, andC₁-C₆alkyl, wherein any 3-6 membered heterocyclyl, 3-6 memberedcarbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, andC₁-C₆alkyl of R^(m) and R^(n) is optionally substituted with R^(w); orR^(m) and R^(n) are taken together with the atom to which they areattached to form a 3-8 membered heterocyclyl that is optionallysubstituted with R^(w); each R^(r) and R^(s) is independently selectedfrom the group consisting of hydrogen, 3-6 membered heterocyclyl, 3-6membered carbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl andC₁-C₃alkyl, wherein any 3-6 membered heterocyclyl, 3-6 memberedcarbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl and C₁-C₃alkylof R^(r) and R^(s) is optionally substituted with R^(v); or R^(r) andR^(s) are taken together with the atom to which they are attached toform a 3-8 membered heterocyclyl or 5-10 membered heteroaryl, which 3-8membered heterocyclyl and 5-10 membered heteroaryl is optionallysubstituted with R^(v); R^(t) and R^(u) are independently selected fromthe group consisting of hydrogen, 3-6 membered heterocyclyl, 3-6membered carbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl andC₁-C₃alkyl, wherein any 3-6 membered heterocyclyl, 3-6 memberedcarbocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl and C₁-C₃alkylof R^(t) and R^(u) is optionally substituted with halo, hydroxy, cyanoor oxo; or R^(t) and R^(u) are taken together with the atom to whichthey are attached to form a 3-6 membered heterocyclyl, optionallysubstituted with halo, hydroxy, cyano or oxo, or C₁-C₆alkyl that isoptionally substituted with halo, hydroxy, cyano or oxo; each R^(v) isindependently selected from the group consisting of halo, hydroxy,cyano, oxo, 6-10 membered aryl, 5-10 membered heteroaryl, C₁-C₆alkyl,C₂-C₃alkenyl, C₂-C₃alkynyl, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl, (6-10 membered aryl)-O—, (5-10 membered heteroaryl)-O—,(3-6 membered carbocyclyl)-O—, (3-6 membered heterocyclyl)-O—, andC₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10 membered heteroaryl,C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 membered heterocyclyl, (6-10membered aryl)-O—, (5-10 membered heteroaryl)-O—, (3-6 memberedcarbocyclyl)-O—, (3-6 membered heterocyclyl)-O—, and C₁-C₆alkoxy ofR^(v) is optionally substituted with halo, hydroxy, cyano, C₁-C₆alkyl,C₂-C₃alkynyl, oxo, 3-6 membered carbocycle, 3-6 membered heterocyclyl,C₁-C₆alkoxy, 5-10 membered heteroaryl or 6-10 membered aryl, each ofwhich is optionally substituted with halo, hydroxy, cyano, oxoC₁-C₃alkyl or C₁-C₃alkoxy; each R^(w) is independently selected from thegroup consisting of halo, hydroxy, cyano, oxo, 6-10 membered aryl, 5-10membered heteroaryl, C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl and C₁-C₆alkoxy, wherein any 6-10 membered aryl, 5-10membered heteroaryl, C₁-C₆alkyl, 3-6 membered carbocyclyl, 3-6 memberedheterocyclyl and C₁-C₆alkoxy of R^(w) is optionally substituted withhalo, hydroxy, cyano, C₁-C₆alkyl, oxo, 3-6 membered carbocyclyl, 3-6membered heterocyclyl C₁-C₆alkoxy, 5-10 membered heteroaryl, or 6-10membered aryl, each optionally substituted with halo, hydroxy, cyano,oxo, C₁-C₃alkyl or C₁-C₃alkoxy; and each R^(x) is independently selectedfrom the group consisting of halo, hydroxy, cyano, nitro, oxo, —OR^(m),—SR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n),—NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), 3-10 membered carbocyclyl, 3-15 memberedheterocyclyl, 6-10 membered aryl, and 5-15 membered heteroaryl, whereinany 3-10 membered carbocyclyl, 3-15 membered heterocyclyl, 6-10 memberedaryl, and 5-15 membered heteroaryl, is optionally substituted with halo,hydroxy, cyano, nitro, C₂-C₆alkenyl, C₂-C₆alkynyl, —OR^(m), —SR^(m),—NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n),—NR^(m)C(O)R^(n), —S(O)₁₋₂R^(m), —NR^(m)S(O)₁₋₂R^(n),—S(O)₁₋₂NR^(m)R^(n), C₁-C₆alkyl, oxo, 3-10 membered carbocyclyl, 3-10membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl,wherein any C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, 3-10 memberedcarbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10membered heteroaryl is optionally substituted with halo, hydroxy, cyano,oxo, —OR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m), —C(O)NR^(m)R^(n),3-6 membered carbocyclyl, 6-10 membered aryl, or C₁-C₆alkyl that isoptionally substituted with halo, hydroxy, cyano, oxo or C₁-C₆alkoxy. 2.A compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R³ is —CH₃.
 3. A compound of claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R³ is —CN.
 4. The compound of claim 1,which is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, which is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, which is a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, which is a compound of Formula (Id):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 or a pharmaceutically acceptable salt thereof, wherein R² is selectedfrom the group consisting of:


9. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R² is cyclopropylcarbonylamino.
 10. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein the group

is selected from the group consisting of:


11. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the group

is selected from the group consisting of:


12. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(a) is selected from the group consisting of:


13. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(a) is selected from the group consisting of:


14. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein: R^(c) is C₁-C₆alkyl that is substituted with R^(x);and R^(x) is selected from the group consisting of 3-10 memberedcarbocyclyl, 3-10 membered heterocycle, 6-10 membered aryl, and 5-10membered heteroaryl, wherein any 3-10 membered carbocyclyl, 3-10membered heterocycle, 6-10 membered aryl, and 5-10 membered heteroarylis optionally substituted with 3-10 membered carbocyclyl, 3-10 memberedheterocycle, 6-10 membered aryl, or 5-10 membered heteroaryl, whereinany 3-10 membered carbocyclyl, 3-10 membered heterocycle, 6-10 memberedaryl, and 5-10 membered heteroaryl is optionally substituted with halo,hydroxy, cyano, oxo, —OR^(m), —NR^(m)R^(n), —C(O)R^(m), —C(O)OR^(m),—C(O)NR^(m)R^(n), or C₁-C₆alkyl that is optionally substituted withhalo, hydroxy, cyano, oxo or C₁-C₆alkoxy.
 15. The compound of claim 1 ora pharmaceutically acceptable salt thereof, wherein R^(c) is selectedfrom the group consisting of:


16. The compound of claim 1 or a pharmaceutically acceptable saltthereof, selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 17. The compound of claim1 or a pharmaceutically acceptable salt thereof, selected from the groupconsisting of:


18. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein the group

is selected from the group consisting of:


19. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(a) is selected from the group consisting of:


20. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(c) is selected from the group consisting of:


21. A pharmaceutical composition comprising a compound of claim 1 or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent or excipient.
 22. A method of preventing,treating or lessening the severity of a disease or condition responsiveto the inhibition of a Janus kinase activity in a patient, comprisingadministering to the patient in need thereof a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically acceptable saltthereof.
 23. The method of claim 22, wherein the disease or condition isasthma.
 24. The method of claim 22, wherein the Janus kinase is JAK1.